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From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease

Gyu Jeong Cho1,*, Sun Myoung Kim1,*, Yoon Mee Yang1orcid, Ekihiro Seki2,3orcid
Clinical and Molecular Hepatology 2026;32(3):1135-1157.
Published online: March 25, 2026

1School of Pharmacy, Sungkyunkwan University, Suwon, Korea

2Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Corresponding authors : Ekihiro Seki, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis Research Bldg., Suite 2099, Los Angeles, CA 90048, USA Tel: +1-310-423-6605, Fax: +1-310-423-0157, E-mail: Ekihiro.Seki@cshs.org
Yoon Mee Yang, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea Tel: +82-31-290-7707, Fax: +82-31-292-8800, E-mail: ymyang@skku.edu

GJC and SMK are the co-first authors and contributed equally to this work.


Editor: Won-Il Jeong, Korea Advanced Institute of Science and Technology, Korea

• Received: December 8, 2025   • Revised: February 26, 2026   • Accepted: March 18, 2026

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently gained attention as a risk factor for primary liver cancer and extrahepatic cancers. Increasing evidence shows that MASLD creates a fibrotic, immunosuppressive tumor microenvironment that supports metastatic growth, making it a risk factor for liver metastasis from extrahepatic tumors, such as colorectal cancer. In steatotic liver, tumor-stromal interactions promote colorectal liver metastasis through several mechanisms, including extracellular vesicles enriched with oncogenic microRNAs, hyaluronan synthase 2-mediated hyaluronic acid production by activated hepatic stellate cells and cancer-associated fibroblasts, M2-polarized tumor-associated macrophage infiltration, and Yes-associated protein-dependent tumor signaling. In this review, we summarize key pathways involved in a pre- and pro-metastatic niche in the liver, such as extracellular vesicle-mediated intercellular communication, feed-forward loops between tumor cells and stromal fibroblasts, and hyaluronic acid-induced extracellular matrix remodeling and immune cell modulation, all of which impair antitumor immunity and promote immune escape. We also discuss how targeting hyaluronic acid synthesis, interleukin-1 signaling, or CXCR2 can restore antitumor immunity and improve responses to programmed cell death protein-1 blockade. These therapeutic approaches may offer promising benefits for patients with colorectal cancer liver metastasis.
  • Keywords: Cancer-associated fibroblast; Extracellular vesicle; Fatty liver; Metastasis; MicroRNA
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most prevalent type of chronic liver disease [1,2]. MASLD increases the risk of extrahepatic cancers, including colorectal cancer (CRC) [3]. This review focuses primarily on CRC due to its high incidence (approximately 80 thousand cases annually in the US, roughly twice the annual incidence of hepatocellular carcinoma), its greater burden compared with liver metastases from other cancers, and its anatomical relationship with the liver via the portal vein [4]. Patients with CRC with underlying MASLD have higher rates of liver metastasis and recurrence than those with normal livers [5-9]. The rising burden of MASLD is creating a major clinical challenge. Steatotic livers develop a tumor-permissive, fibrotic, and immunosuppressive microenvironment [10-12]. In MASLD, injured hepatocytes release damage-associated molecular patterns and inflammatory signals that lead to inflammation and abnormal deposition of extracellular matrix (ECM) [13]. In MASLD, excessive cancer-promoting extracellular vesicles (EVs), particularly those carrying pathogenic microRNAs; cancer-associated fibroblast (CAF) activation; hyaluronic acid (HA) production; and aberrant Hippo/Yes-associated protein (YAP) signaling contributes to the development of a fibrotic and immunosuppressive tumor microenvironment [11,14]. This review discusses how MASLD creates a pre- and pro-metastatic niche and highlights therapeutic implications.
Pathophysiological features of steatotic liver
MASLD covers a wide range of liver changes, from simple steatosis to the inflammatory and fibrotic stage of metabolic dysfunction-associated steatohepatitis (MASH) [15]. Lipid overload and endoplasmic reticulum stress cause hepatocyte injury and trigger the release of inflammatory mediators [16,17]. Chronic inflammation activates quiescent hepatic stellate cells (HSCs) into myofibroblasts that produce ECM, leading to fibrosis [18]. The deposition of fat establishes a hepatic microenvironment to support chronic inflammation and fibrogenesis that enhance metastasis.
Clinical and preclinical evidence supporting increased liver metastasis
Clinical studies show that MASLD predisposes patients to liver metastases (Table 1). Patients with hepatic steatosis exhibit worse overall and hepatic recurrence-free survival in the presence of fibrosis [5]. In a prospective cohort of 2,715 patients who underwent resection of CRC liver metastases, those with steatosis had worse disease-free survival [6]. The prevalence of synchronous CRC liver metastasis at diagnosis is higher in MASLD patients than in non-MASLD controls, identifying MASLD as an independent risk factor [9]. Another retrospective study also demonstrated that the incidence of liver metastasis was higher in patients in the MASLD group than in those in the non-MASLD group [19]. Moreover, hepatic steatosis is associated with an increased risk of metachronous colorectal liver metastases after CRC resection [20] and in patients with established liver metastases, MASLD and related metabolic abnormalities have been identified as independent adverse prognostic factors for overall survival [21-23]. While a number of studies suggest a pro-metastatic environment [5-7,9,20,24-29], others report no or a lesser impact of hepatic steatosis on the development of CRC liver metastases [30-33]. These discrepancies may be due to differences in study design, patient selection, and endpoints. For example, contradictory results may also arise from the limited sensitivity of imaging-based assessments (e.g., computed tomography or ultrasonography) in detecting mild steatosis [30-33].
Despite contradictory clinical reports on CRC liver metastasis, the biological evidence is strong, as preclinical models consistently demonstrate that progression of MASLD enhances liver metastasis (Table 2). High-fat diet (HFD)-induced steatosis generates a tumor-permissive microenvironment [10,12,34]. MASLD conditions also promote expansion of immunosuppressive regulatory T cells, the generation of PD-1 high exhausted T cells, and the recruitment of myeloid-derived suppressor cells, facilitating CRC liver metastasis and poor response to anti-PD-1 therapy [26,35]. MASH models with fibrosis show a pro-metastatic effect. For example, mice fed a choline-deficient, L-amino acid-defined HFD develop steatohepatitis and fibrosis, which leads to an increased number of CRC liver metastases [36]. Western diet-induced steatotic livers also exhibit impaired anti-tumor immunity [35]. Consistently, genetically induced mouse models demonstrated that MASLD enhances liver metastasis by promoting tumor-hepatocyte metabolic crosstalk [37]. Altogether, progression from simple steatosis to steatohepatitis with fibrosis reinforces both stromal and immune changes that increase liver metastasis.
The MASLD microenvironment is characterized by chronic endogenous metabolic stress and lipotoxicity, leading to immunological remodeling involving M1/M2 macrophage shifts and Th1/Treg dysregulation, which impairs anti-tumor immunosurveillance [14]. Conversely, the pro-metastatic niche is shaped by extra- and intrahepatic crosstalk, which triggers T cell exhaustion and neutrophil recruitment in alcoholic liver disease [38]. This review focuses on MASLD, for which there is growing clinical and preclinical evidence of its contribution to liver metastasis.
Pre- and pro-metastatic reprogramming of liver niche
Recent cancer research increasingly focuses on the tumor microenvironment and its role in forming a “premetastatic niche” or “prometastatic niche.” Before metastases develop, primary tumors alter distant organs by releasing soluble factors and EVs, priming the target organ’s microenvironment permissive for metastatic colonization and tumor growth [39,40]. During this stage, resident immune cells, such as Kupffer cells, exhibit an M1-like phenotype, releasing pro-inflammatory and pro-fibrogenic cytokines that transdifferentiate quiescent HSCs into myofibroblasts [39,40].
Conversely, the post-metastatic liver undergoes immune reprogramming, shifting from a pro-inflammatory state to an immunosuppressive condition that facilitates tumor growth. The immunosuppressive microenvironment is reinforced by the infiltration of M2-polarized tumor-associated macrophages (TAMs), TREM2+ secreted phosphoprotein 1 (SPP1)+ lipid-associated macrophages (LAMs), the recruitment of CXCR2+ MDSCs, and the dominance of α-smooth muscle actin (α-SMA)+ myofibroblastic CAFs (my-CAFs) [11,26,41].
MASLD exacerbates the formation of a metastasis-permissive microenvironment in the liver [14]. In MASLD, the liver is enriched with lipids and inflammatory mediators that reprogram resident hepatic and infiltrating cells toward prometastatic phenotypes. For example, the lipid-rich MASLD microenvironment increases intracellular palmitate levels and the palmitoylation of epidermal growth factor receptor, which is essential for maintaining cancer stemness and metastatic potential [34]. The fibrotic stroma, rich in collagen and HA, facilitates tumor cell adhesion and growth while transmitting signals promoting survival and proliferation [11].
In MASLD, the immune microenvironment shifts toward immunosuppression, with an accumulation of M2-polarized TAMs that secrete interleukin (IL)-10 and TGF-β [12]. Concurrently, anti-tumor T cells are reduced in number or function by overexpression of immune checkpoint molecules, such as PD-1, thereby weakening the immune system’s ability to control tumor growth [35]. This immunosuppressive environment, combined with stromal fibrosis, provides a fibrotic, inflamed, and immunologically tumor-permissive microenvironment that acts as both a pre- and pro-metastatic niche [11,12,14].
EVs are small, membrane-bound particles (including exosomes, 30–150 nm) secreted by cells into the extracellular space [42]. EV-mediated communication has a key role in establishing the metastatic niche, enabling crosstalk among the primary tumor, liver hepatocytes, stromal cells, and immune cells [39,40,43]. MASLD alters both EV production and cargo, which contributes to metastasis [44,45].
Hepatocyte-derived EVs promote metastatic potential in MASLD
Lipotoxicity increases hepatocyte EV secretion and alters their cargo composition [14,46-50]. In the steatotic liver, intracellular lipid accumulation alters the molecular machinery of EV biogenesis [46]. Rab27a is upregulated in MASLD livers, supporting its role in enhanced EV secretion under steatotic conditions (Fig. 1A) [14]. Rab27a-dependent hepatocyte EV release is responsible for HFD-induced CRC liver metastasis [14].
Steatotic liver also reprograms EV cargo loading, enriching EVs with pathogenic molecules that influence cancer cells and immune cells in the tumor microenvironment [14]. Table 3 provides a summary of hepatocyte-derived EV-microRNAs that are upregulated in the steatotic liver microenvironment and their verified targets involved in metastatic progression. In the MASLD microenvironment, fat-laden hepatocyte-derived EVs deliver specific microRNAs (miR-25, miR-92a, and miR-103) that establish a highly permissive prometastatic niche even before CRC cells are delivered to the liver [14]. These microRNAs enhance oncogenic YAP signaling by targeting large tumor suppressor kinase 2 (LATS2), which in turn enhances cancer cell growth and induces the secretion of cysteine-rich protein 61 (CYR61) [14,51-53]. This signaling axis ultimately promotes an immunosuppressive microenvironment by inducing M2 macrophage infiltration (Fig. 1A). Table 3 lists other microRNAs, such as miR-151a-3p and the miR-221-3p/222-3p cluster, which are consistently upregulated in the blood of MASLD patients, HFD-fed mice, and HFD-fed mice bearing liver metastasis, and palmitic acid-treated primary hepatocytes [14]. While established literature confirms their ability to promote liver metastasis through targets like SP3 and SPINT1, their direct causal role in steatosis-induced metastasis remains to be elucidated [54-56].
Beyond microRNAs, other hepatocyte EV cargo also contributes to metastasis. To date, neuron navigator 2 (NAV2) represents a notable proteomic cargo specifically demonstrated to drive steatosis-associated CRC liver metastasis beyond microRNA-mediated mechanisms. HFD or high-fructose diet increases hepatic Golgi protein 73 (GP73), which promotes lipid accumulation and enhances CRC liver metastasis [57]. GP73 increases EV production by binding cholesterol, promoting multivesicular body formation, and altering hepatocyte EV proteome (Fig. 1A). GP73 also induces secretion of NAV2-enriched EVs, and serum GP73 correlates with EV NAV2 in patients with CRC with liver metastasis (Fig. 1A). EVs from GP73-high hepatocytes increase CRC invasiveness and metastatic potential [57].
Tumor-derived EVs as key mediators of hepatic steatosis, immune suppression, and premetastatic niche formation
Primary tumor cells release EVs that can travel to distant organs, including the liver, and contribute to premetastatic niche formation. EVs from highly metastatic CRC induce hepatic lipid accumulation through enhanced fatty acid synthesis, promoting steatosis and metastatic spread [58]. Tumor-derived EVs and particles, containing palmitate, also induce liver metabolic dysfunction by triggering TNF secretion from Kupffer cells, leading to inflammatory and steatotic changes [43]. Tumor-derived EVs can also establish a premetastatic niche independent of fatty liver conditions. For instance, studies have shown that pancreatic ductal adenocarcinoma-derived EVs enriched with macrophage migration inhibitory factor or specific exosomal integrins are taken up by Kupffer cells and other resident cells [39,59]. This interaction triggers TGF-β secretion and upregulates fibronectin production by HSCs, creating a fibrotic and immunosuppressive microenvironment.
Tumor-derived EV microRNAs, especially EV-miR-25-3p, mediate forming the premetastatic niche by modulating vascular and immune components in distant organs [60]. EV-miR-25-3p, released from CRC cells, promotes metastasis by remodeling the vascular environment [60]. EV-miR-25-3p increases vascular permeability by downregulating tight junction proteins and enhances endothelial cell proliferation and tube formation via targeting KLF2 and KLF4, ultimately promoting angiogenesis [60]. When taken up by hepatic macrophages, EVs enriched in miR-25-3p, miR-130b-3p, and miR-425-5p induce M2-type polarization, creating an immunosuppressive microenvironment favorable for tumor colonization and growth (Fig. 1B) [61].
Tumor EVs further modulate immune and stromal compartments. Tumor-derived EV-miR-934 polarizes macrophages toward an immunosuppressive M2 phenotype via the PTEN/PI3K/AKT pathway and increases metastatic tumor burden [62]. Highly metastatic CRC EVs also alter immune cell infiltration, increasing neutrophils and SPP1+ LAMs, while decreasing resident Kupffer cells [58]. SPP1+ LAMs promote tumor progression by stimulating fibroblast-mediated EV release and T-cell exhaustion [41].
Tumor-derived EVs also activate HSCs, the precursors of hepatic CAFs [63]. Highly metastatic CRC cells secrete miR-181a-5p-enriched EVs and miR-188-3p-enriched EVs, which are taken up by HSCs and promote their activation [64,65]. miR-181a-5p suppresses SOCS3 and activates the IL-6/STAT3 pathway, resulting in HSC transdifferentiation and ECM remodeling [65]. Activated HSCs release CCL20, which acts on CRC cells, upregulating miR-181a-5p and forming a positive feedback loop [65]. miR-188-3p directly targets PHLPP2, activates the AKT/mTOR pathway, and induces α-SMA expression and enhanced HSC migration [64]. Activated HSCs remodel the ECM and promote CRC invasion, forming a pro-metastatic liver microenvironment. Another study reveals that CRC-derived EVs are enriched with the ribosome biogenesis protein HSPC111 [66]. These EVs are taken up by HSCs in the liver premetastatic niche. Following EV delivery, HSPC111 interacts with and phosphorylates ATP-citrate lyase in CAFs. This metabolic reprogramming upregulates CXCL5 in CAFs and promotes CRC cell migration and invasion. Cancer cell-derived EVs induce fibroblast differentiation into myofibroblasts, stromal remodeling and cancer progression [67]. Cancer cell-derived EVs loaded with miR-1290 activate normal fibroblasts into inflammatory CAFs (iCAFs), which show higher levels of mitophagy and mitochondrial DNA transfer [68].
CRC cells secrete EVs enriched with miR-221/222, which are taken up by recipient CRC cells and other cell types in the tumor microenvironment [55]. miR-221/222 upregulate hepatocyte growth factor (HGF) [55]. Tumor-derived miR-221/222 helps establish a premetastatic niche that promotes CRC invasiveness [55].
Altogether, tumor-derived EVs, particularly those from highly metastatic CRC, induce hepatic steatosis, immune remodeling, HSC activation, and CAF reprogramming (Fig. 1B). Tumor EVs utilize distinct cargo to prime the liver for metastasis via both steatosis-dependent and independent pathways.
HSCs and CAFs as a source of pro-fibrotic and tumor-supportive EVs
HSCs are the principal ECM-producing cells in the liver and a major source of CAFs in metastatic tumors [11,63]. Recent findings indicate that activated HSCs release EVs that propagate fibrogenesis and CAF activity in the metastatic niche. For example, HSC-derived EVs carry platelet-derived growth factor receptor-α (PDGFRα), which promotes HSC activation through SHP2-dependent mechanisms [69]. Uptake of PDGFRα-enriched EVs by recipient HSCs stimulates migration and activation, amplifying fibrogenic responses in the liver (Fig. 1B) [69].
CAFs also promote tumor progression through EVs. CAF-derived EVs are taken up by CRC cells and increase proliferation, migration, invasion, and metastatic potential [70]. miR-92a-3p stimulates Wnt/β-catenin signaling and stemness while enhancing epithelial-mesenchymal transition (EMT) and reducing mitochondrial apoptosis by targeting FBXW7 and MOAP1 [70]. CAF-derived EV-miR-21 is abundant and transferred to CRC cells, enhancing proliferation and chemoresistance [71]. These findings indicate that stromal EV-miR-21 directly promotes CRC liver metastasis by modulating the tumor microenvironment and enhancing the metastatic capacity. While other components, such as proteins, lipids or lncRNAs, likely play critical roles in niche remodeling, their specific contributions remain largely unexplored in the context of steatosis-promoted metastasis. Further investigations are expected to uncover key EV mediators in the future.
HSCs as the origin of CAFs
HSCs, portal fibroblasts, mesothelial cells, bone marrow-derived fibrocytes, and resident fibroblasts have been considered as potential origins of CAFs. In CRC liver metastasis, most CAFs originated from HSCs [63]. Upon HFD feeding and tumor implantation, TdTomato+ CAFs, which specifically label HSC-derived cells, further increased within metastatic lesions, supporting the enrichment of HSC-derived CAFs in metastatic tumors of steatotic livers [11,63].
Tumor-derived factors are major drivers of HSC-to-CAF transition [39,72,73]. Tumor-derived TGF-β is a potent mediator of HSC differentiation into CAFs [74]. Beyond cytokines, recent spatial transcriptomics and single-cell analyses have identified SPP1 as a pivotal driver of this transition [75]. In steatotic liver, HSCs are more readily activated by these tumor-derived factors, making them more prone to transdifferentiating into CAFs and promoting metastatic outgrowths.
CAF subtypes in steatotic liver
Recent single-cell RNA sequencing studies have identified distinct CAF subpopulations, including myCAFs, which are α-SMA+ and ECM-producing with contractile properties [63,76,77]; iCAFs, which secrete cytokines and growth factors [63,76,78]; and a less common antigen-presenting subtype (apCAFs) characterized by the expression of MHC class II-related molecules (Table 4) [76,79,80]. Among them, myCAFs are a major constituent of the metastatic niche [63,81]. Notably, imaging mass cytometry analyses of CRC liver metastasis patients with MASLD demonstrate a marked expansion of myCAFs compared to non-MASLD patients [11]. iCAFs produce HGF, which enhances tumor growth [63]. apCAFs may modulate T-cell activity through antigen presentation, potentially contributing to the immunosuppressive state [82].
These CAF subtypes have distinct functions in CRC liver metastasis. myCAF-derived HA and iCAF-derived HGF support tumor growth, whereas myCAF-produced type I collagen forms a mechanical barrier that restrains tumor expansion independent of stiffness (Fig. 2) [63]. HA is a ubiquitous nonsulfated glycosaminoglycan of the ECM, synthesized by hyaluronan synthase (HAS). Among HAS isoforms, HAS2 is greatly induced in MASLD-associated myCAFs, resulting in the pathological accumulation of low-molecular-weight HA (LMW-HA) within the liver metastatic niche, which actively promotes tumor progression [11]. Depleting CAFs or knocking out Has2 in HSCs reduces metastatic burden and improves survival in mouse models of desmoplastic liver metastases.
While myCAF-derived HA drives metastasis, the overall impact of CAFs is highly context-dependent. Excessive collagen deposition and cross-linking-mediated lysyl oxidase increase ECM stiffness [83]. This mechanical shift activates mechanotransduction pathways, such as the YAP axis, which promotes EMT and tumor cell survival [84]. In colorectal liver metastasis, studies have shown that HSC-specific Col1a1 deficiency promotes CRC metastatic tumor growth, indicating a tumor-suppressive role for type I collagen [63]. High-density collagen acts as a physical barrier that restricts the expansion of metastatic colonies and limits the infiltration of immunosuppressive cells (Fig. 2A) [63]. Importantly, this tumor-restraining role in metastasis contrasts with primary hepatocellular carcinoma, where myCAF-derived collagen actively promotes tumor development. A similar paradox is observed with iCAF-derived HGF, which promotes liver metastasis but has been shown to suppress primary hepatocellular carcinoma development [85]. These findings suggest that CAFs exert both pro- and anti-tumorigenic roles in a subtype- and context-dependent manner.
iCAFs secrete soluble factors, such as HGF and secreted frizzled-related protein 1 (SFRP1) [63,86]. Genetic deletion of Hgf in HSCs significantly reduces metastatic progression [63]. SFRP1 interacts with FGFR2 to stabilize HIF-1. These pathways induce expression of EMT-related genes and stemness markers, facilitating increased tumor migration, invasion, and proliferation (Fig. 2B) [86]. Another study identified Fos-driven complement factor D (CFD)+ iCAFs as key pro-metastatic contributors in CRC [86]. These CFD+ iCAFs are enriched in metastatic CRC tumors and associated with poor prognosis and increased EMT and stemness features [86]. Their secreted factor SFRP1 promotes liver metastasis through FGFR2-HIF1 signaling (Fig. 2B) [86].
In the context of MASLD, scRNA-seq of liver metastases revealed that steatotic livers not only increase the total number of CAFs but also shift their phenotype [11]. Our group found that diet-induced steatosis doubled the number of intratumoral CAFs in a CRC metastasis model. Notably, a specific CAF subpopulation upregulated HAS2 and the HA receptor CD44 under HFD conditions [11]. This suggests that steatosis favors an HA-producing CAF subset that supports tumor growth.
HA, a major ECM component, undergoes dynamic turnover by HAS and hyaluronidases, generating high-molecular-weight HA (HMW-HA) and HA fragments with distinct biological activities. HA mediates tumor cell growth, migration, invasion, metastasis, and immune evasion through receptors, such as CD44, toll-like receptor 4 (TLR4) and TLR2, receptor for hyaluronan-mediated motility (RHAMM), and lymphatic vessel endothelial receptor 1 (LYVE-1) (Fig. 3A). CD44, a principal HA receptor broadly expressed in many tumor types, enhances cellular adhesion, motility, invasion, and metastatic dissemination [87]. Mechanistically, LMW-HA binds to CD44 and stimulates key signaling pathways, including PI3K/AKT, MAPK, and TGF-β, promoting EMT, migration, and invasion [88-91]. The variant isoform CD44v6 promotes CRC stem cell colonization, invasion, and metastasis by acting as a co-receptor for growth factors such as HGF and CXCL12, thereby activating receptor tyrosine kinase and PI3K/AKT signaling [88]. High expression of CD44 or CD44v6 correlates with poor prognosis and increased metastatic potential [88,92,93].
TLR4 and TLR2 are activated in tumors by HA fragments generated during tissue injury, chronic inflammation, and tissue remodeling [94,95]. Activation of these receptors promotes inflammation, increases cell motility and proliferation, inhibits apoptosis, and stimulates secretion of factors that facilitate metastasis [95-98]. In tumor cells, TLR4 and TLR2 signaling are associated with aggressive phenotypes and support an immunosuppressive environment [99-101]. RHAMM expression increases in advanced cancer stages [102]. Upon interacting with LMW-HA, RHAMM promotes tumor cell proliferation through ERK and β-catenin pathways and has been linked to invasiveness, metastasis, and poor prognosis [103-106]. RHAMM also contributes to angiogenesis within the tumor microenvironment [107]. LYVE-1 also interacts with HA within the tumor microenvironment [108,109]. Tumor-derived HA fragments, especially LMW-HA, promote lymphangiogenesis through LYVE-1. The binding of these fragments triggers internalization of sphingosine-1-phosphate receptor 1 and activates the Src signaling pathway, facilitating lymphangiogenic responses, such as endothelial cell proliferation, migration, and tube formation [109]. LYVE-1 may mediate lymphatic vessel remodeling, enhance tumor cell entry into lymphatic channels, and promote dissemination to regional lymph nodes.
Taken together, LMW-HA and its receptor-mediated signaling reprogram the tumor microenvironment toward a pro-metastatic, immunosuppressive, and lymphangiogenic niche.
HAS2-driven HA synthesis in steatotic tumor microenvironment
Metastatic tumors from patients with CRC with MASLD exhibit higher HA levels than those from patients without MASLD [11]. Consistent with this observation, tumor-bearing mice fed an HFD showed marked elevation of HA levels in both serum and metastatic liver tumors. Among HA synthases, HAS2 was the most upregulated isoform in these tumors, with increased Has2 mRNA specifically in HSC-derived CAFs [11].
HA’s biological functions vary by molecular size. HAS2 assembles a repeating disaccharide of glucuronic acid and N-acetylglucosamine to generate HMW-HA [110]. In pathological states, HMW-HA is rapidly fragmented into LMW-HA by hyaluronidases, TMEM2, or reactive oxygen species [111-113]. HMW-HA (>1,000 kDa) typically protects tissues from injury, whereas LMW-HA (<100 kDa) promotes tumor cell growth, invasion, and angiogenesis (Fig. 3B) [11,112,114]. Steatotic tumors exhibit a higher proportion of LMW-HA relative to HMW-HA [11].
HAS2-mediated HA production enhances tissue stiffness, modulates immune-cell infiltration, and promotes a pro-tumorigenic milieu. Inhibiting HAS2 expression or enzymatic activity reduces fibrosis, decreases collagen and HA deposition, and limits tumor-associated ECM remodeling [11,115]. In the HFD-associated CRC liver metastasis model, genetic deletion of Has2 in HSCs (Has2ΔHSC) provided strong evidence for the protumorigenic role of HA. HFD-fed Has2ΔHSC mice showed markedly reduced metastatic tumor growth. These findings demonstrate that HSC-derived HA is a key driver of the fibrotic, immunosuppressive tumor microenvironment in steatotic livers.
HA-mediated YAP activation in steatotic tumor microenvironment
Matrix stiffness enhanced by HA activates mechanotransduction pathways, such as the Hippo/YAP pathway, which transmits pro-survival and proliferative signals to tumor cells. YAP activity is controlled by post-translational modifications within the Hippo kinase cascades. MST1/2 phosphorylate LATS1/2, which in turn phosphorylate YAP at serine 127, promoting 14-3-3-dependent cytosolic retention, and at serine 381, triggering β-TRCP-dependent ubiquitination and proteasomal degradation [116-119]. Mechanical cues and stress conditions promote YAP nuclear translocation, where it functions as a transcriptional coactivator regulating genes involved in cell proliferation, survival, and tumor progression [116].
The Hippo-YAP pathway is crucial for MASLD-associated liver metastasis. EV-mediated YAP activation drives metastatic tumor growth, and HA-CD44 interactions further increase YAP activity in cancer cells [11,14]. LMW-HA promotes YAP nuclear translocation through focal adhesion kinase (FAK), which activates Src-dependent phosphorylation of YAP at tyrosine 357 [11,120]. FAK also promotes YAP activity by inhibiting phosphorylation of MOB1, an essential activator of LATS1/2 kinases [117]. Notably, HA molecular weight differentially regulates Hippo signaling [11,121]. In breast cancer, HMW-HA acts as a tumor-suppressor by activating Hippo signaling, whereas LMW-HA inhibits Hippo activation. HMW-HA induces CD44 clustering and PAR1b-dependent MST activation. In contrast, LMW-HA binds CD44 without inducing CD44 clustering, thereby preventing PAR1b recruitment and Hippo activation [121,122].
In HFD-induced steatotic livers, metastatic CRC cells exhibit increased nuclear YAP and elevated expression of YAP target genes, including connective tissue growth factor (CTGF)/CCN2 and CYR61/CCN1, indicating strong YAP activation in fatty livers compared with normal livers [11,14]. HSC-derived HAS2 increases HA deposition, and LMWHA enhances YAP activity in CRC cells, leading to increased expression of YAP targets that further remodel the tumor microenvironment. CTGF from YAP-activated tumor cells upregulates HAS2 in CAFs, creating a positive feedback loop (HAS2-HA-YAP-CTGF) that reinforces HA production and sustains YAP activation in metastases (Fig. 2A) [11].
Together, ECM stiffness-driven mechanotransduction pathways, EV-derived YAP regulation, and HA receptor-mediated signaling establish a convergent signaling network that drives metastatic tumor growth and immune evasion in MASLD-associated liver metastasis.
Angiogenesis and vascular permeability
In the steatotic liver niche, angiogenesis is primarily driven by the metabolic reprogramming of the immune microenvironment. Specifically, M2-polarized TAMs serve as a source of VEGF [12]. This process is orchestrated by the activation of NLRC4 inflammasome within macrophages, which triggers IL-1β signaling to sustain high levels of VEGF secretion, thereby promoting neovascularization and supporting metastatic outgrowth (Fig. 4). Following the establishment of metastases, the tumor cells emerge as an additional source of VEGF.
The metabolic characteristics of the steatotic liver may further exacerbate vascular remodeling. For instance, the accumulation of LMW-HA in the niche has the potential to stimulate endothelial cells via LYVE-1 and RHAMM, receptors known to mediate lymphangiogenesis and tube formation in other contexts [107-109]. Furthermore, as listed in Table 3, steatotic hepatocytes secrete EVs enriched with miR-25-3p. While its direct impact in this specific setting warrants further investigation, miR-25-3p is known to target KLF2 and KLF4 in endothelial cells [60], which may enhance vascular permeability and facilitate tumor cell extravasation.
Immunosuppressive environment in CRC liver metastasis
In MASLD-associated liver metastasis, tumor progression occurs within a stromal environment enriched in immune checkpoints and profoundly exhausted cytotoxic T cells. M2-polarized TAMs, largely derived from LAMs, express high levels of PD-L1 and TIM-3, while CD8⁺ T cells upregulate PD-1, TIM-3, and VISTA, leading to profound T cell exhaustion [11,14]. In patients with MASLD, regulatory T cells exhibit elevated PD-1/PD-L1 and increased VISTA and TIM-3, indicating a checkpoint-rich, immunosuppressive landscape [11,14].
Our study shows that the HAS2-HA-CD44-YAP axis contributes to an immunosuppressive tumor microenvironment. scRNA-seq and spatial imaging mass cytometry analyses revealed that HAS2high CAFs strongly interact with M2d-like TAMs and CD8+ T cells in HFD-induced tumors. These TAMs display high expression of CD44 and PD-L1, and CD8+ T cells express elevated PD-1 [11].
In parallel, hepatocyte-derived EVs loaded with oncogenic microRNAs (miR-25, miR-92a, and miR-103) activate YAP signaling in tumor cells (Fig. 1A). Activated YAP upregulates CYR61, which recruits and polarizes M2-TAMs in the steatotic liver [14]. Concomitantly, PD1+ CD8+ T cells in HFD tumors show increased exhaustion markers. Silencing of Yap1 in tumor cells reversed these immunosuppressive features, demonstrating the importance of the EVYAP-CYR61-TAM axis in shaping the immunosuppressive tumor microenvironment [14].
Additionally, lipid-induced inflammasome activation further reinforces the immunosuppressive and angiogenic phenotype. In HFD-induced MASLD, metastatic CRC tumors show markedly increased F4/80+ CD206+ M2-TAMs and inflammasome components [11,12,14]. Although Nlrc4 deficiency does not alter steatosis or early tumor engraftment, it reduces M2-TAM infiltration, Th2 cytokines, IL-1β secretion, VEGF levels, and angiogenesis, thereby limiting metastatic tumor growth. The recruitment of immunosuppressive myeloid populations is further facilitated by chemokine signaling. In MASLD, metabolic stress triggers Kupffer cells to secrete CXCL5, which acts as a critical ligand for CXCR2-expressing MDSCs [26]. The resulting accumulation of CXCR2+ MDSCs within the metastatic niche not only suppresses T-cell activity but also establishes a therapeutic barrier that confers resistance to PD-1 blockade [26].
Collectively, MASLD remodels the immune microenvironment by inducing tumor-intrinsic YAP activation, EV-mediated macrophage recruitment, inflammasome signaling, and chemokine signals. These converging pathways expand immunosuppressive myeloid populations, exhausted cytotoxic lymphocytes, and establish a highly pro-metastatic tumor microenvironment.
HAS/HA inhibitors
4-Methylumbelliferone (4-MU), approved in Europe and Asia for the treatment of biliary spasm, inhibits HA synthesis [123]. Given that HA production depends on the availability of UDP‑glucuronic acid and UDP-N-acetylglucosamine [124], 4-MU acts as a competitive substrate of UDP-glucuronosyltransferase (UGT) and inhibits HA synthesis [123]. 4-MU also downregulates the mRNA expression of HAS, UDP-glucose pyrophosphorylase, and dehydrogenase, enzymes required for generating HA precursors [125]. 4-MU is rapidly conjugated with glucuronic acid by UGT to form 4-methylumbelliferyl glucuronide (4-MUG), which can be converted to 4-MU intracellularly. Both 4-MU and 4-MUG efficiently inhibit HA synthesis.
Pharmacologically, 4-MU exerts anti-steatotic, anti-inflammatory, and anti-fibrotic effects in MASLD. In a choline-deficient, L-amino acid diet-induced MASH model, oral 4-MU reduced total and LMW-HA, improved steatosis, and attenuated hepatocellular injury, inflammatory cytokines, macrophage infiltration, and fibrogenesis [126]. Preclinical studies also show that 4-MU suppresses HA-rich ECM, reduces tumor cell adhesion, and enhances responses to chemotherapy and immunotherapy [127].
4-MU (hymecromone) is currently in early-phase clinical testing. Clinical trials have demonstrated that oral hymecromone is relatively safe [128]. Importantly, 4-MU provides a dose-dependent and reversible inhibition of HA synthesis [123]. However, potential off-target effects on systemic glucuronidation remain a critical consideration, particularly for long-term therapeutic applications.
In the steatotic liver-CRC model, pharmacologic inhibition of HA synthesis with 4-MU or 4-MUG suppressed metastatic tumor growth, reduced HA and collagen deposition, and decreased CAF infiltration [11]. Given that these changes correlate with decreased α-SMA expression and ECM remodeling, they suggest a targeted reduction in the myCAF phenotype. However, the specific effects of 4-MU on other subtypes, such as iCAFs or apCAFs, have yet to be elucidated and require further research. Beyond its impact on the fibroblast-HA axis, 4-MU acts as a regulator of the metastatic niche. Studies have demonstrated that 4-MU treatment attenuates M2 macrophages and leads to a significant decrease in cancer stem cell markers [11,129]. Notably, combining anti-PD-1 therapy with 4-MU improved anti-PD-1 efficacy under HFD conditions [11]. Thus, modulating the fibrotic microenvironment may improve the effectiveness of immune checkpoint therapy.
IL-1 receptor antagonist
Given the important role of IL-1-mediated inflammasome activation in MASLD-associated CRC liver metastasis, IL-1 blockade is an emerging therapeutic strategy [12]. Anakinra, a recombinant IL-1 receptor antagonist approved for the treatment of rheumatoid arthritis, competitively inhibits IL-1α/IL-1β binding to the IL-1 receptor, thereby suppressing downstream inflammatory signaling [12,130].
In a CRC liver metastasis model, anakinra reduced metastatic tumor growth under HFD conditions, whereas it showed no antitumor activity in mice on a normal diet [12]. The tumor-suppressive effect in steatotic livers correlated with a marked reduction in M2-TAM infiltration, while hepatic lipid accumulation remained unchanged [12]. These results suggest that IL-1 signaling is critical for M2-TAM recruitment and metastatic progression in MASLD. Thus, pharmacological inhibition of IL-1 with anakinra reduces CRC liver metastasis in MASLD primarily by limiting IL-1-dependent TAM infiltration and immunosuppressive niche formation [12]. In CRC-stromal crosstalk, tumor-derived IL-1α stimulates CXCL12 production in fibroblasts, whereas IL-1 receptor antagonist reduces CXCL12 secretion and downstream CXCL12/CXCR4-dependent endothelial migration, proliferation, and angiogenesis, thereby attenuating CRC metastatic potential [131]. These results support further exploration of anakinra as an adjunct to existing cancer therapies in patients with MASLD with liver metastasis. However, despite its therapeutic potential, the clinical application of anakinra has several limitations and adverse effects [132]. Anakinra can increase the risk of serious infections and neutropenia due to the cytokine’s fundamental role in innate immunity.
CXCR1/2 inhibitors
CXCR1/2 inhibitors emerge as a promising strategy to counteract the MASLD-induced recruitment of CXCR2+ MDSCs described above [133]. Aberrant activation of the CXCL5/CXCR2 axis in steatotic livers facilitates the infiltration of these immunosuppressive myeloid cells [26]. MASLD increases the infiltration of CXCR2+ MDSCs through Kupffer cell-derived CXCL5, which enhances CRC liver metastasis and confers resistance to PD-1 blockade [26]. Pharmacological antagonists inhibit this myeloid recruitment. In preclinical models, CXCR1/2 antagonists reduced CRC liver metastases [133]. CXCR2 inhibitors, such as AZD5069 and reparixin, improved the effectiveness of anti-PD-1 in MASH-related hepatocellular carcinoma and MASLD-associated CRC liver metastasis, respectively [26,134]. Overall, these findings highlight CXCR1/2 blockade as a promising strategy to restore antitumor immunity and enhance immune checkpoint inhibitor efficacy in MASLD-associated liver metastasis. However, the systemic use of CXCR1/2 inhibitors is frequently limited by the induction of neutropenia [135]. Therefore, clinical application requires a precise balance between inhibiting immunosuppressive myeloid recruitment and maintaining systemic innate immunity.
MASLD reshapes the liver niche into a pre- and pro-metastatic environment that is permissive to metastatic tumor growth and resistant to immunotherapy. In steatotic livers, hepatocyte-derived EVs carrying oncogenic microRNAs, altered tumor-intrinsic signaling, such as YAP activation, and CAF-driven stromal remodeling collectively create a pro-metastatic liver microenvironment. The altered tumor milieu, characterized by M2-TAM infiltration, T-cell exhaustion, and CAF-mediated HA production, generates a fibrotic, immunosuppressive tumor microenvironment that promotes CRC metastasis and confers resistance to anti-PD-1 therapy (Fig. 4).
Emerging preclinical studies in MASLD-associated liver metastasis have highlighted potential therapeutic targets, including HA synthesis, IL-1 signaling, and CXCR1/2 signaling. Although MASLD-associated CRC liver metastases exhibit resistance to anti-PD-1 monotherapy, combination regimens pairing immune checkpoint inhibitors with 4-MU or CXCR2 inhibitors can restore antitumor immunity. Targeting metabolic dysfunction, stromal remodeling, and immune suppression may serve as an effective integrated therapeutic strategy for MASLD-driven metastatic tumors.

Authors’ contribution

Y.M.Y. and E.S. conceived and designed the study, G. J.C., S.M.K., Y.M.Y. and E.S. drafted and revised the manuscript, and Y.M.Y. and E.S. obtained the funding. G.J.C., S.M.K., and Y.M.Y. prepared the figures and tables. All authors have read and approved the final version of the manuscript.

Acknowledgements

This work is supported by the National Institutes of Health (P01CA233452, R01CA301632, R01DK085252, and R01DK138591 to E.S.), by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (RS-2023-00210489, RS-2024-00441114, and RS-2024-00454443 to Y.M.Y.). This paper was supported by SKKU Academic Research Support Program (Samsung Research Fund), Sungkyunkwan University, 2025. The illustrations were created with BioRender.com.

Conflicts of Interest

The authors have no conflicts to disclose.

Figure 1.
Extracellular vesicle-mediated cell-to-cell communication in the steatotic liver tumor microenvironment. (A) In steatotic hepatocytes, RAB27A and GP73 expression are upregulated, promoting MVB formation and EV secretion. Hepatocyte-derived EVs from steatotic liver deliver oncogenic microRNAs (such as miR-25-3p, miR-92a-3p, and miR-103-3p) and proteins (such as NAV2) to colorectal cancer cells, suppressing LATS kinases, activating nuclear YAP, and inducing YAP target genes (CYR61 and CTGF) to drive EMT, proliferation, and immune suppression. (B) In steatotic liver, metastatic tumor-derived EVs mediate multidirectional crosstalk among tumor cells, Kupffer cells, dendritic cells, tumor-associated macrophages, and hepatic stellate cells. EVs enriched in palmitic acid released from tumor cells activate Kupffer cells to secrete TNF, which in turn regulates dendritic cells. EV-associated microRNAs from tumor cells promote the PI3K/AKT pathway in macrophages, promoting M2 polarization and an immunosuppressive milieu. In parallel, tumor-derived EV-microRNAs and hepatic stellate cell-derived EVs carrying PDGFRα cooperate to activate hepatic stellate cells, further reinforcing fibrotic remodeling and metastatic outgrowth. AKT, protein kinase B; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; EMT, epithelial-mesenchymal transition; EV, extracellular vesicle; GP73, Golgi protein 73; IL, interleukin; LATS, large tumor suppressor kinase; miR, microRNA; MVB, multivesicular body; NAV2, neuron navigator 2; PDGFRα, platelet-derived growth factor receptor alpha; PI3K, phosphoinositide 3-kinase; Rab, ras-associated binding; TNF, tumor necrosis factor; YAP, Yes-associated protein.
cmh-2025-1389f1.jpg
Figure 2.
Distinct roles of myofibroblastic CAFs and inflammatory CAFs in shaping the tumor microenvironment. (A) Myofibroblastic CAFs produce abundant collagen, creating a stiff mechanical barrier around the tumor. CAF-derived hyaluronic acid engages CD44 on tumor cells, activating FAK, which inhibits the Hippo kinase cascade and stabilizes nuclear YAP, leading to TEAD-dependent induction of YAP target genes, such as CYR61 and CTGF. This hyaluronic acid-CD44-FAK-YAP axis promotes tumor cell proliferation and contributes to immune suppression. (B) Inflammatory CAFs secrete growth factors and Wnt modulators, including HGF and SFRP1, which signal through MET and FGFR2 on tumor cells to activate ERK and AKT pathways and upregulate HIF-1-induced EMT-related genes. These signals induce transcription factors ZEB and SNAIL and increase expression of stemness and invasion markers (such as CD133, CD44), enhancing tumor cell proliferation, EMT, migration, and invasion. AKT, protein kinase B; CAF, cancer-associated fibroblast; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FGFR2, fibroblast growth factor receptor 2; HGF, hepatocyte growth factor; HIF-1, hypoxia-inducible factor 1; MET, mesenchymal-epithelial transition factor; SFRP1, secreted frizzled-related protein 1; SNAIL, snail family transcriptional repressor 1; TEAD, TEA domain transcription factor; YAP, Yes-associated protein; ZEB, zinc finger E-box-binding homeobox.
cmh-2025-1389f2.jpg
Figure 3.
Hyaluronic acid receptors, HA size, and HA synthases in the tumor microenvironment. (A) Major HA receptors and their downstream signaling pathways. CD44 activates MAPK and PI3K/AKT cascades to drive epithelial-mesenchymal transition, migration, and invasion. TLR2/4 signal via MyD88-dependent NF-κB signaling to promote inflammation, proliferation, and an immunosuppressive milieu. LYVE-1 signaling supports lymphangiogenesis, proliferation, migration, and tube formation. RHAMM engages β-catenin signaling to enhance invasion, metastasis, and angiogenesis. (B) HA size classes, turnover, and biosynthesis. HA synthases (HAS1-3) polymerize UDPGlcA and UDP-GlcNAc into HA chains of different lengths. HAS2 predominantly produces HMW-HA, which is progressively cleaved by HYALs and TMEM2 into LMW-HA and HA oligos in the extracellular space. AKT, protein kinase B; HA, hyaluronic acid; HAS, hyaluronan synthase; HMW-HA, high molecular weight HA; HYAL, hyaluronidases; LMW-HA, low molecular weight HA; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphoinositide 3-kinase; RHAMM, receptor for hyaluronan-mediated motility; TLR2/4, toll-like receptor 2/4; TMEM2, transmembrane protein 2; UDP-GlcA, uridine diphosphate glucuronic acid; UDPGlcNAc, uridine diphosphate N-acetylglucosamine.
cmh-2025-1389f3.jpg
Figure 4.
MASLD-driven pre- and pro-metastatic niche in colorectal cancer liver metastasis. The schematic illustrates how MASLD reshapes the liver into a pre- and pro-metastatic niche that accelerates metastatic tumor growth compared with a non-steatotic liver. Within the MASLD liver, four major processes cooperatively support liver metastasis: (a) EV-mediated cell-to-cell crosstalk, (b) immunosuppression, (c) ECM remodeling, and (d) angiogenesis and vascular permeability. CAF, cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; CXCL, C-X-C motif chemokine ligand; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EV, extracellular vesicle; IL, interleukin; MASLD, metabolic dysfunction-associated steatotic liver disease; MDSC, myeloid-derived suppressor cell; MMP2, matrix metalloproteinase 2; NK, natural killer; NLRC4, NLR family CARD domain containing 4; Palm, palmitic acid; TAM, tumor-associated macrophage; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; Treg, regulatory T cell.
cmh-2025-1389f4.jpg
Table 1.
Clinical studies of steatosis-associated colorectal cancer liver metastasis
Table 1.
Study Patient cohort Group Steatosis Clinical outcomes References
Chen et al. CRLM patients receiving curative-intent therapy (hepatectomy and/ or radiofrequency ablation) Steatosis (n=39) vs. no steatosis (n=156) 20.0% (39/195) had hepatic steatosis; among these, 61.5% also had fibrosis Hepatic steatosis predicts worse overall recurrence-free survival (HR 1.86, 95% CI 1.23–2.82; P=0.003) and hepatic recurrence-free survival (HR 2.07, 95% CI 1.33–3.22; P=0.001); in steatosis patients, fibrosis is associated with further reduction in overall and hepatic RFS. [5]
Hamady et al. Patients undergoing primary resection of colorectal liver metastases Steatosis (n=902) vs. no steatosis (n=902); propensity-matched 34.1% (927/2,715) had hepatic steatosis Hepatic steatosis is an independent predictor of local hepatic recurrence (HR 1.28, 95% CI 1.11–1.47; P=0.0005); local liver disease-free survival consistently worse in the steatosis group; overall survival numerically worse but not statistically significant (HR 1.08, P=0.13). [6]
Lv and Zhang Newly diagnosed colorectal cancer patients (n=451) evaluated retrospectively at a single center MASLD (n=60) vs. no MASLD (control, n=391) 13.3% (60/451) had MASLD Prevalence of synchronous CRLM: 18.33% in MASLD vs. 7.42% in controls; MASLD was an independent risk factor for synchronous CRLM (OR 3.93, 95% CI 1.62–9.56). [9]
Miyata et al. Patients with colorectal cancer undergoing curative (radical) surgery (n=388) MASLD fibrosis score–defined MASLD (n=45) vs. non-MASLD (n=343) MASLD group 45/388 (11.6%); fibrosis defined by MASLD fibrosis score cut-off Liver metastasis: 17.8% in MASLD group (8/45) vs. 5.0% in non-MASLD group (17/343), P=0.004; Liver metastasis–free survival significantly worse in MASLD group (P<0.001). [19]
Dai et al. Cohort of patients undergoing colorectal cancer surgery Steatosis (n=97) vs. no steatosis (n=317) 30.9% steatosis in patients who later developed metachronous CRLM; 15.9% steatosis in recurrence-free patients Hepatic steatosis associated with increased risk of metachronous CRLM (OR 1.99, 95% CI 1.19–3.30; P=0.008); fibrotic liver further increases risk (OR 4.27, 95% CI 1.54–11.81; P=0.005). [20]
van Dijk et al. Partial hepatectomy for colorectal liver metastases Steatosis (n=135) vs. no steatosis (n=83) MASLD present in 62% of patients MASLD associated with shorter overall survival (HR 1.8, 95% CI 1.0–3.0); increasing myosteatosis (HR 1.8, 95% CI 1.1–2.9) and skeletal muscle loss (HR 1.7, 95% CI 1.0–2.9) are independent adverse prognostic factors. [21]

CI, confidence interval; CRLM, colorectal cancer liver metastasis; HR, hazard ratio; MASLD, metabolic dysfunction-associated steatotic liver disease; OR, odds ratio; RFS, recurrence-free survival.

Table 2.
Preclinical studies of steatosis-associated colorectal cancer liver metastasis
Table 2.
Preclinical model Model details Effect on colorectal cancer liver metastasis References
Diet-induced mouse model
 MASL
  High-fat diet (HFD) • Diet: HFD (60% kcal from fat) for 8 weeks • HFD-induced fatty liver increases the CRC liver metastases, with marked accumulation of M2-polarized tumor-associated macrophages and cancer-associated fibroblasts within metastatic foci. [11,12,14]
• Metastasis: 2×105 MC38 cells injected into spleen; analysis at 14 days
 MASH
  CDAHFD • Diet: CDAHFD (0.1% methionine, no choline, 60% fat), 4 or 6 weeks • Moderate fatty liver (4-week CDAHFD) activates anti-tumor immunity (M1 macrophages, CD8+ T cells) and suppresses metastatic growth. [36]
• Metastasis: 1×105 CT26 cells injected into spleen; analysis at 14–15 days • Severe fatty liver (6-week CDAHFD) promotes invasion and metastasis.
  Western diet • Diet: Western diet (50.5% kcal from fat, high sucrose/fructose, 1.25% cholesterol, reduced choline), fed for 1–4 months. • Western diet–induced MASH increases hepatic inflammation and fibrosis, impairs cytotoxic CD8+ T cell and NK cell infiltration and function within metastatic foci, and thereby enhances CRC liver metastases. [35]
• Metastasis: 5×104 MC38 cells injected into spleen; analysis at 14 days
Genetically induced mouse model
 Leptin-/-mice (ob/ob) • Mice: age 8–16 weeks. • Leptin deficiency creates an obesogenic, immunosuppressed milieu, impairs immune surveillance, and increases the incidence and growth of CRC liver metastases. [37]
• Metastasis: Systemic (left ventricular) injection of 1×105 PyMT-Bo1-GFP-Luc or B16 melanoma cells.
 Fat free (FF) mice • Mice: FF mice were generated by crossing homozygous Lox-stop-Lox-ROSA-DTA mice with adipoq-Cre Tg mice. • Lack of brown adipose tissue and thermoneutral housing promote a lipid-rich hepatic microenvironment, macrophage polarization, and suppression of cytotoxic T cells, thereby enhancing CRC liver metastasis. [37]
• Metastasis: Same tumor protocols as above.
 Adipoq-Cre, PPARγfl/fl • Mice: Adipocyte-specific PPARγ deletion mice generated by mating PPARγfl/fl mice with adipoq-Cre. • Adipocyte-specific PPARγ deletion increases inflammatory cytokines and alters leptin signaling, which enhances cancer stemness, migration, EMT, and metastatic colonization in the liver. [37]
• Metastasis: Same tumor protocols as above.

CDAHFD, choline-deficient L-amino acid-defined high-fat diet; CRC, colorectal cancer; DTA, diphtheria toxin a; EMT, epithelial–mesenchymal transition; MASH, metabolic dysfunction-associated steatohepatitis; MASL, metabolic dysfunction-associated steatotic liver.

Table 3.
List of hepatocyte-derived EV microRNAs upregulated in MASLD and their mechanisms promoting liver metastasis
Table 3.
MicroRNA Primary tumor Recipient cell type(s) Target gene(s) Mechanism promoting liver metastasis References
miR-25-3p CRC Endothelial cell KLF2/KLF4 • Angiogenesis and vascular permeability (↑ VEGFR, tight junction-related proteins) [60]
TAM PTEN • M2-TAM polarization via PTEN/PI3K/Akt pathway [61]
• Angiogenesis (VEGF secretion ↑)
• EMT
CRC cell LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
miR-92a-3p CRC CRC cell FBXW7 • Wnt/β-catenin pathway [70]
• Stemness and EMT
• Chemotherapy resistance
MOAP1 • Inhibition of mitochondrial apoptosis
• Apoptotic proteins & cytochrome c release ↓
• Chemotherapy resistance
LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
miR-103-3p CRC CRC cell LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
DAPK • Migration and invasion [56]
KLF4 • Cell-matrix adhesion ↑
• Cell-cell adhesion ↓
• Colonization of CRC cells
miR-151a-3p Gastric cancer Kupffer cell SP3 • SP3 ↓ → TGF-β/SMAD signaling ↑ [54]
YTHDF3 • YTHDF3 ↓ → SUMO1 ↓ → SP3 ↓
• Stem cell-like properties and EMT
miR-221-3p/miR-222-3p CRC Liver stromal cell SPINT1 • HGF ↑ [55]

CRC, colorectal cancer; CYR61, cysteine-rich angiogenic inducer 61; DAPK, death-associated protein kinase; EMT, epithelial-tomesenchymal transition; EV, extracellular vesicle; FBXW7, F-BOX/WD repeat-containing protein 7; HGF, hepatocyte growth factor; KLF, Krüppel-like factor; LATS2, large tumor suppressor kinase 2; MASLD, metabolic dysfunction-associated steatotic liver disease; miR, microRNA; MOAP1, modulator of apoptosis 1; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SPINT1, serine protease inhibitor Kunitz type 1; SUMO1, small ubiquitin-related modifier 1; TAM, tumor-associated macrophage; TGF-β, transforming growth factor-beta; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt, wingless and Int-1; YAP, Yes-associated protein; YTHDF3, YTH N6-methyladenosine RNA binding protein 3.

Table 4.
Cancer-associated fibroblast subtype and role in cancer
Table 4.
CAF Marker Secretory factor Major role in cancer References
myCAF • Col1a1 • Collagen • ECM remodeling [63,76,77]
• Col1a2 • HA • Collagen deposition
• Acta2 • TGF-β • Angiogenesis
• Mmp2 • IL-4
• Col15a1 • IL-13
iCAF • Hgf • IL-6 • Inflammation [63,76,78]
• Bmp10 • IL-11 • Immune cell recruitment
• H2-Q4 • IL-8 • Immune cell suppression
• Ifitm1 • LIF
• Gdf2 • GM-CSF
• H2-Q7 • CXCLs
• CCLs
apCAF • CD74 • CXCL-12 • Antigen-presenting [76,79,80]
• HLA-DRA • CXCL-14 • Regulatory T cell differentiation
• HLA-DPA1 • CFD
• HLA-DPB1
• POSTN

Acta2, actin alpha 2, smooth muscle; apCAF, antigen-presenting cancer-associated fibroblast; Bmp10, bone morphogenetic protein 10; CFD, complement factor D;Col15a1, collagen type XV alpha 1 chain; Col1a1, collagen type I alpha 1 chain; Col1a2, collagen type I alpha 2 chain; CXCL, C-X-C motif chemokine ligand; ECM, extracellular matrix; Gdf2, growth differentiation factor 2; GM-CSF, granulocyte-macrophage colony-stimulating factor; H2-Q4, histocompatibility 2, Q region locus 4; H2-Q7, histocompatibility 2, Q region locus 7; HA, hyaluronic acid; Hgf, hepatocyte growth factor; HLA-DPA1, major histocompatibility complex, class II, DP alpha; HLA-DPB1, major histocompatibility complex, class II, DP beta; HLA-DRA, major histocompatibility complex, class II, DR alpha; iCAF, inflammatory cancer-associated fibroblast; Ifitm1, Interferon induced transmembrane protein 1; IL, interleukin; Mmp2, matrix metallopeptidase 2; myCAF, myofibroblastic cancer-associated fibroblast; POSTN, periostin; TGF-β, transforming growth factor-beta.

apCAF

antigen presenting cancer-associated fibroblast

α-SMA

alpha-smooth muscle actin

CAF

cancer-associated fibroblast

CFD

complement factor D

CRC

colorectal cancer

CTGF

connective tissue growth factor

CYR61

cysteine-rich protein 61

ECM

extracellular matrix

EMT

epithelial-mesenchymal transition

EV

extracellular vesicle

FAK

focal adhesion kinase

GP73

Golgi protein 73

HA

hyaluronic acid

HAS

hyaluronan synthase

HFD

high-fat diet

HGF

hepatocyte growth factor

HMW-HA

high molecular weight hyaluronic acid

HSC

hepatic stellate cell

iCAF

inflammatory cancer-associated fibroblast

LAM

lipid-associated macrophage

LATS

large tumor suppressor kinase

LMW-HA

low molecular weight hyaluronic acid

LYVE-1

lymphatic vessel endothelial receptor 1

MASH

metabolic dysfunction-associated steatohepatitis

MASLD

metabolic dysfunction-associated steatotic liver disease

miR

microRNA

4-MU

4-methylumbelliferone

4-MUG

4-methylumbelliferyl glucuronide

myCAF

myofibroblastic cancer-associated fibroblast

NAV2

neuron navigator 2

PDGFRα

platelet-derived growth factor receptor α

RHAMM

receptor for hyaluronanmediated motility

SFRP1

secreted frizzled-related protein 1

SPP1

secreted phosphoprotein 1

TAM

tumor-associated macrophage

TLR

toll-like receptor

UGT

UDPglucuronosyltransferase

YAP

yes-associated protein
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From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease
Clin Mol Hepatol. 2026;32(3):1135-1157.   Published online March 25, 2026
DOI: https://doi.org/10.3350/cmh.2025.1389
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From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease
Clin Mol Hepatol. 2026;32(3):1135-1157.   Published online March 25, 2026
DOI: https://doi.org/10.3350/cmh.2025.1389
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From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease
Image Image Image Image
Figure 1. Extracellular vesicle-mediated cell-to-cell communication in the steatotic liver tumor microenvironment. (A) In steatotic hepatocytes, RAB27A and GP73 expression are upregulated, promoting MVB formation and EV secretion. Hepatocyte-derived EVs from steatotic liver deliver oncogenic microRNAs (such as miR-25-3p, miR-92a-3p, and miR-103-3p) and proteins (such as NAV2) to colorectal cancer cells, suppressing LATS kinases, activating nuclear YAP, and inducing YAP target genes (CYR61 and CTGF) to drive EMT, proliferation, and immune suppression. (B) In steatotic liver, metastatic tumor-derived EVs mediate multidirectional crosstalk among tumor cells, Kupffer cells, dendritic cells, tumor-associated macrophages, and hepatic stellate cells. EVs enriched in palmitic acid released from tumor cells activate Kupffer cells to secrete TNF, which in turn regulates dendritic cells. EV-associated microRNAs from tumor cells promote the PI3K/AKT pathway in macrophages, promoting M2 polarization and an immunosuppressive milieu. In parallel, tumor-derived EV-microRNAs and hepatic stellate cell-derived EVs carrying PDGFRα cooperate to activate hepatic stellate cells, further reinforcing fibrotic remodeling and metastatic outgrowth. AKT, protein kinase B; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; EMT, epithelial-mesenchymal transition; EV, extracellular vesicle; GP73, Golgi protein 73; IL, interleukin; LATS, large tumor suppressor kinase; miR, microRNA; MVB, multivesicular body; NAV2, neuron navigator 2; PDGFRα, platelet-derived growth factor receptor alpha; PI3K, phosphoinositide 3-kinase; Rab, ras-associated binding; TNF, tumor necrosis factor; YAP, Yes-associated protein.
Figure 2. Distinct roles of myofibroblastic CAFs and inflammatory CAFs in shaping the tumor microenvironment. (A) Myofibroblastic CAFs produce abundant collagen, creating a stiff mechanical barrier around the tumor. CAF-derived hyaluronic acid engages CD44 on tumor cells, activating FAK, which inhibits the Hippo kinase cascade and stabilizes nuclear YAP, leading to TEAD-dependent induction of YAP target genes, such as CYR61 and CTGF. This hyaluronic acid-CD44-FAK-YAP axis promotes tumor cell proliferation and contributes to immune suppression. (B) Inflammatory CAFs secrete growth factors and Wnt modulators, including HGF and SFRP1, which signal through MET and FGFR2 on tumor cells to activate ERK and AKT pathways and upregulate HIF-1-induced EMT-related genes. These signals induce transcription factors ZEB and SNAIL and increase expression of stemness and invasion markers (such as CD133, CD44), enhancing tumor cell proliferation, EMT, migration, and invasion. AKT, protein kinase B; CAF, cancer-associated fibroblast; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FGFR2, fibroblast growth factor receptor 2; HGF, hepatocyte growth factor; HIF-1, hypoxia-inducible factor 1; MET, mesenchymal-epithelial transition factor; SFRP1, secreted frizzled-related protein 1; SNAIL, snail family transcriptional repressor 1; TEAD, TEA domain transcription factor; YAP, Yes-associated protein; ZEB, zinc finger E-box-binding homeobox.
Figure 3. Hyaluronic acid receptors, HA size, and HA synthases in the tumor microenvironment. (A) Major HA receptors and their downstream signaling pathways. CD44 activates MAPK and PI3K/AKT cascades to drive epithelial-mesenchymal transition, migration, and invasion. TLR2/4 signal via MyD88-dependent NF-κB signaling to promote inflammation, proliferation, and an immunosuppressive milieu. LYVE-1 signaling supports lymphangiogenesis, proliferation, migration, and tube formation. RHAMM engages β-catenin signaling to enhance invasion, metastasis, and angiogenesis. (B) HA size classes, turnover, and biosynthesis. HA synthases (HAS1-3) polymerize UDPGlcA and UDP-GlcNAc into HA chains of different lengths. HAS2 predominantly produces HMW-HA, which is progressively cleaved by HYALs and TMEM2 into LMW-HA and HA oligos in the extracellular space. AKT, protein kinase B; HA, hyaluronic acid; HAS, hyaluronan synthase; HMW-HA, high molecular weight HA; HYAL, hyaluronidases; LMW-HA, low molecular weight HA; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphoinositide 3-kinase; RHAMM, receptor for hyaluronan-mediated motility; TLR2/4, toll-like receptor 2/4; TMEM2, transmembrane protein 2; UDP-GlcA, uridine diphosphate glucuronic acid; UDPGlcNAc, uridine diphosphate N-acetylglucosamine.
Figure 4. MASLD-driven pre- and pro-metastatic niche in colorectal cancer liver metastasis. The schematic illustrates how MASLD reshapes the liver into a pre- and pro-metastatic niche that accelerates metastatic tumor growth compared with a non-steatotic liver. Within the MASLD liver, four major processes cooperatively support liver metastasis: (a) EV-mediated cell-to-cell crosstalk, (b) immunosuppression, (c) ECM remodeling, and (d) angiogenesis and vascular permeability. CAF, cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; CXCL, C-X-C motif chemokine ligand; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EV, extracellular vesicle; IL, interleukin; MASLD, metabolic dysfunction-associated steatotic liver disease; MDSC, myeloid-derived suppressor cell; MMP2, matrix metalloproteinase 2; NK, natural killer; NLRC4, NLR family CARD domain containing 4; Palm, palmitic acid; TAM, tumor-associated macrophage; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; Treg, regulatory T cell.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease
Study Patient cohort Group Steatosis Clinical outcomes References
Chen et al. CRLM patients receiving curative-intent therapy (hepatectomy and/ or radiofrequency ablation) Steatosis (n=39) vs. no steatosis (n=156) 20.0% (39/195) had hepatic steatosis; among these, 61.5% also had fibrosis Hepatic steatosis predicts worse overall recurrence-free survival (HR 1.86, 95% CI 1.23–2.82; P=0.003) and hepatic recurrence-free survival (HR 2.07, 95% CI 1.33–3.22; P=0.001); in steatosis patients, fibrosis is associated with further reduction in overall and hepatic RFS. [5]
Hamady et al. Patients undergoing primary resection of colorectal liver metastases Steatosis (n=902) vs. no steatosis (n=902); propensity-matched 34.1% (927/2,715) had hepatic steatosis Hepatic steatosis is an independent predictor of local hepatic recurrence (HR 1.28, 95% CI 1.11–1.47; P=0.0005); local liver disease-free survival consistently worse in the steatosis group; overall survival numerically worse but not statistically significant (HR 1.08, P=0.13). [6]
Lv and Zhang Newly diagnosed colorectal cancer patients (n=451) evaluated retrospectively at a single center MASLD (n=60) vs. no MASLD (control, n=391) 13.3% (60/451) had MASLD Prevalence of synchronous CRLM: 18.33% in MASLD vs. 7.42% in controls; MASLD was an independent risk factor for synchronous CRLM (OR 3.93, 95% CI 1.62–9.56). [9]
Miyata et al. Patients with colorectal cancer undergoing curative (radical) surgery (n=388) MASLD fibrosis score–defined MASLD (n=45) vs. non-MASLD (n=343) MASLD group 45/388 (11.6%); fibrosis defined by MASLD fibrosis score cut-off Liver metastasis: 17.8% in MASLD group (8/45) vs. 5.0% in non-MASLD group (17/343), P=0.004; Liver metastasis–free survival significantly worse in MASLD group (P<0.001). [19]
Dai et al. Cohort of patients undergoing colorectal cancer surgery Steatosis (n=97) vs. no steatosis (n=317) 30.9% steatosis in patients who later developed metachronous CRLM; 15.9% steatosis in recurrence-free patients Hepatic steatosis associated with increased risk of metachronous CRLM (OR 1.99, 95% CI 1.19–3.30; P=0.008); fibrotic liver further increases risk (OR 4.27, 95% CI 1.54–11.81; P=0.005). [20]
van Dijk et al. Partial hepatectomy for colorectal liver metastases Steatosis (n=135) vs. no steatosis (n=83) MASLD present in 62% of patients MASLD associated with shorter overall survival (HR 1.8, 95% CI 1.0–3.0); increasing myosteatosis (HR 1.8, 95% CI 1.1–2.9) and skeletal muscle loss (HR 1.7, 95% CI 1.0–2.9) are independent adverse prognostic factors. [21]
Preclinical model Model details Effect on colorectal cancer liver metastasis References
Diet-induced mouse model
 MASL
  High-fat diet (HFD) • Diet: HFD (60% kcal from fat) for 8 weeks • HFD-induced fatty liver increases the CRC liver metastases, with marked accumulation of M2-polarized tumor-associated macrophages and cancer-associated fibroblasts within metastatic foci. [11,12,14]
• Metastasis: 2×105 MC38 cells injected into spleen; analysis at 14 days
 MASH
  CDAHFD • Diet: CDAHFD (0.1% methionine, no choline, 60% fat), 4 or 6 weeks • Moderate fatty liver (4-week CDAHFD) activates anti-tumor immunity (M1 macrophages, CD8+ T cells) and suppresses metastatic growth. [36]
• Metastasis: 1×105 CT26 cells injected into spleen; analysis at 14–15 days • Severe fatty liver (6-week CDAHFD) promotes invasion and metastasis.
  Western diet • Diet: Western diet (50.5% kcal from fat, high sucrose/fructose, 1.25% cholesterol, reduced choline), fed for 1–4 months. • Western diet–induced MASH increases hepatic inflammation and fibrosis, impairs cytotoxic CD8+ T cell and NK cell infiltration and function within metastatic foci, and thereby enhances CRC liver metastases. [35]
• Metastasis: 5×104 MC38 cells injected into spleen; analysis at 14 days
Genetically induced mouse model
 Leptin-/-mice (ob/ob) • Mice: age 8–16 weeks. • Leptin deficiency creates an obesogenic, immunosuppressed milieu, impairs immune surveillance, and increases the incidence and growth of CRC liver metastases. [37]
• Metastasis: Systemic (left ventricular) injection of 1×105 PyMT-Bo1-GFP-Luc or B16 melanoma cells.
 Fat free (FF) mice • Mice: FF mice were generated by crossing homozygous Lox-stop-Lox-ROSA-DTA mice with adipoq-Cre Tg mice. • Lack of brown adipose tissue and thermoneutral housing promote a lipid-rich hepatic microenvironment, macrophage polarization, and suppression of cytotoxic T cells, thereby enhancing CRC liver metastasis. [37]
• Metastasis: Same tumor protocols as above.
 Adipoq-Cre, PPARγfl/fl • Mice: Adipocyte-specific PPARγ deletion mice generated by mating PPARγfl/fl mice with adipoq-Cre. • Adipocyte-specific PPARγ deletion increases inflammatory cytokines and alters leptin signaling, which enhances cancer stemness, migration, EMT, and metastatic colonization in the liver. [37]
• Metastasis: Same tumor protocols as above.
MicroRNA Primary tumor Recipient cell type(s) Target gene(s) Mechanism promoting liver metastasis References
miR-25-3p CRC Endothelial cell KLF2/KLF4 • Angiogenesis and vascular permeability (↑ VEGFR, tight junction-related proteins) [60]
TAM PTEN • M2-TAM polarization via PTEN/PI3K/Akt pathway [61]
• Angiogenesis (VEGF secretion ↑)
• EMT
CRC cell LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
miR-92a-3p CRC CRC cell FBXW7 • Wnt/β-catenin pathway [70]
• Stemness and EMT
• Chemotherapy resistance
MOAP1 • Inhibition of mitochondrial apoptosis
• Apoptotic proteins & cytochrome c release ↓
• Chemotherapy resistance
LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
miR-103-3p CRC CRC cell LATS2 • YAP activity ↑ [14]
• CYR61 production ↑
• Immunosuppressive TME (M2-TAM recruitment and CD8+ T cell exhaustion)
DAPK • Migration and invasion [56]
KLF4 • Cell-matrix adhesion ↑
• Cell-cell adhesion ↓
• Colonization of CRC cells
miR-151a-3p Gastric cancer Kupffer cell SP3 • SP3 ↓ → TGF-β/SMAD signaling ↑ [54]
YTHDF3 • YTHDF3 ↓ → SUMO1 ↓ → SP3 ↓
• Stem cell-like properties and EMT
miR-221-3p/miR-222-3p CRC Liver stromal cell SPINT1 • HGF ↑ [55]
CAF Marker Secretory factor Major role in cancer References
myCAF • Col1a1 • Collagen • ECM remodeling [63,76,77]
• Col1a2 • HA • Collagen deposition
• Acta2 • TGF-β • Angiogenesis
• Mmp2 • IL-4
• Col15a1 • IL-13
iCAF • Hgf • IL-6 • Inflammation [63,76,78]
• Bmp10 • IL-11 • Immune cell recruitment
• H2-Q4 • IL-8 • Immune cell suppression
• Ifitm1 • LIF
• Gdf2 • GM-CSF
• H2-Q7 • CXCLs
• CCLs
apCAF • CD74 • CXCL-12 • Antigen-presenting [76,79,80]
• HLA-DRA • CXCL-14 • Regulatory T cell differentiation
• HLA-DPA1 • CFD
• HLA-DPB1
• POSTN
Table 1. Clinical studies of steatosis-associated colorectal cancer liver metastasis

CI, confidence interval; CRLM, colorectal cancer liver metastasis; HR, hazard ratio; MASLD, metabolic dysfunction-associated steatotic liver disease; OR, odds ratio; RFS, recurrence-free survival.

Table 2. Preclinical studies of steatosis-associated colorectal cancer liver metastasis

CDAHFD, choline-deficient L-amino acid-defined high-fat diet; CRC, colorectal cancer; DTA, diphtheria toxin a; EMT, epithelial–mesenchymal transition; MASH, metabolic dysfunction-associated steatohepatitis; MASL, metabolic dysfunction-associated steatotic liver.

Table 3. List of hepatocyte-derived EV microRNAs upregulated in MASLD and their mechanisms promoting liver metastasis

CRC, colorectal cancer; CYR61, cysteine-rich angiogenic inducer 61; DAPK, death-associated protein kinase; EMT, epithelial-tomesenchymal transition; EV, extracellular vesicle; FBXW7, F-BOX/WD repeat-containing protein 7; HGF, hepatocyte growth factor; KLF, Krüppel-like factor; LATS2, large tumor suppressor kinase 2; MASLD, metabolic dysfunction-associated steatotic liver disease; miR, microRNA; MOAP1, modulator of apoptosis 1; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SPINT1, serine protease inhibitor Kunitz type 1; SUMO1, small ubiquitin-related modifier 1; TAM, tumor-associated macrophage; TGF-β, transforming growth factor-beta; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt, wingless and Int-1; YAP, Yes-associated protein; YTHDF3, YTH N6-methyladenosine RNA binding protein 3.

Table 4. Cancer-associated fibroblast subtype and role in cancer

Acta2, actin alpha 2, smooth muscle; apCAF, antigen-presenting cancer-associated fibroblast; Bmp10, bone morphogenetic protein 10; CFD, complement factor D;Col15a1, collagen type XV alpha 1 chain; Col1a1, collagen type I alpha 1 chain; Col1a2, collagen type I alpha 2 chain; CXCL, C-X-C motif chemokine ligand; ECM, extracellular matrix; Gdf2, growth differentiation factor 2; GM-CSF, granulocyte-macrophage colony-stimulating factor; H2-Q4, histocompatibility 2, Q region locus 4; H2-Q7, histocompatibility 2, Q region locus 7; HA, hyaluronic acid; Hgf, hepatocyte growth factor; HLA-DPA1, major histocompatibility complex, class II, DP alpha; HLA-DPB1, major histocompatibility complex, class II, DP beta; HLA-DRA, major histocompatibility complex, class II, DR alpha; iCAF, inflammatory cancer-associated fibroblast; Ifitm1, Interferon induced transmembrane protein 1; IL, interleukin; Mmp2, matrix metallopeptidase 2; myCAF, myofibroblastic cancer-associated fibroblast; POSTN, periostin; TGF-β, transforming growth factor-beta.

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Table 4.

Clin Mol Hepatol : Clinical and Molecular Hepatology
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