Hepatocellular carcinoma (HCC) remains a formidable clinical therapeutic challenge due to its profound molecular and immunologic heterogeneity [
1]. Despite advances with multikinase inhibitors and immune checkpoint blockade, the clinical efficacy of MET inhibitors has been modest at best [
2,
3]. Although both selective and non-selective MET inhibitors have been evaluated in advanced HCC after sorafenib failure, cabozantinib, non-selective MET inhibitor, remains the only FDA-approved agent showing clinical benefit in CELESTIAL trial, while tivantinib, selective MET inhibitor, failed due to off-target toxicities related to microtubule interruption and lack of efficacy in METIV-HCC trial [
4,
5]. The suboptimal clinical outcomes are likely attributable to incomplete inhibition of MET signaling and the activation of compensatory pathways. Given that c-MET overexpression is observed in approximately 25% of HCC cases, increasing to nearly 80% in advanced stages, highlighting the need for more effective and durable MET-targeted strategies.
In this issue of
Clinical and Molecular Hepatology, Wang et al. [
6] provide compelling mechanistic insights into MET-driven hepatocarcinogenesis by identifying a previously unrecognized MET-TRIB3-FOXO1 signaling axis. In an
in vivo hydrodynamic tail vein injection (HTVi) model that cointroduced MET and β-catenin plasmids into murine hepatocytes, the authors performed RNA-sequencing of liver tumors and uncovered significant upregulation of TRIB3. This finding was further supported by gene ontology (GO) and gene set enrichment analysis (GSEA), which revealed that TRIB3 was associated with key oncogenic pathways, including mitogen-activated protein kinase (MAPK) signaling. Importantly, analysis of TCGA LIHC cohort confirmed that TRIB3 expression positively correlated with MET pathway activation and poor patient prognosis, lending strong translational relevance to the murine model data.
The authors identify TRIB3, a member of the tribbles pseudokinase family, as a key effector of MET-driven hepatocarcinogenesis and comprehensively delineated a novel oncogenic axis in HCC progression. TRIB3 has been increasingly recognized as a key contributor to oncogenesis in various malignancies, including breast, lung, gastric, colorectal cancers, and hepatocellular carcinoma [
7]. Notably, one study using TRIB3-overexpressing Huh7 cells reported a significant association with TRIB3 and the expression of RAF, MEK, and ERK, key mediators of MAPK signaling driving cellular growth, proliferation, and metastasis [
8].
To determine the mechanistic role of TRIB3 in HCC progression, the authors employed both gain- and loss-of-function strategies in vitro and in vitro, demonstrating that TRIB3 enhances proliferation, migration, and metastasis of HCC cells. Proteomic analysis of TRIB3 immunoprecipitates via mass spectrometry identified several candidate binding partners, among which the E3 ubiquitin ligase COP1 was prominently enriched. Further bioinformatic protein–protein interaction mapping using the STRING database highlighted COP1 as a central interactor. Follow-up validation with co-immunoprecipitation and confocal microscopy confirmed that TRIB3 physically interacts with COP1 in the nucleus of HCC cells.
TRIB3 recruits COP1 to the tumor suppressor FOXO1, facilitating FOXO1 solidifying the role of this axis in TRIB3 induction ubiquitination and proteasomal degradation. The loss of FOXO1 relieves its transcriptional repression on key oncogenic drivers such as MET, CTNNB1 (β-catenin), and TWIST1, establishing a positive feedback loop that further amplifies HCC progression.
FOXO1, a well-established tumor suppressor, orchestrates cellular apoptosis, cell cycle arrest, and oxidative stress responses. Its degradation is a hallmark of aggressive tumor phenotypes in HCC, and the current study identifies TRIB3 as a pivotal molecular bridge linking MET signaling to FOXO1 destabilization [
9]. This mechanistic insight not only elucidates the oncogenic function of TRIB3 but also explains how MET activation may evade direct inhibition by establishing compensatory downstream loops.
To elucidate the upstream regulation of TRIB3, the authors used luciferase promoter assays and truncation/mutagenesis constructs, revealing that MET induces TRIB3 transcription via the ERK–SP1 axis. Chromatin immunoprecipitation (ChIP) and pharmacological inhibition experiments confirmed that ERK activation increases SP1 binding to the TRIB3 promoter, solidifying the role of this axis in inducing TRIB3. Critically, therapeutic intervention using hepatocyte-specific AAV8-shTRIB3—an adeno-associated viral vector known for liver-targeted, long-term gene expression—significantly suppressed MET-driven tumor growth and lung metastasis in vitro, underscoring the clinical feasibility of TRIB3-targeted strategies. This liver-directed strategy restored FOXO1 expression and inhibited downstream oncogenes, highlighting the translational feasibility of targeting TRIB3 to disrupt MET-driven HCC.
Clinically, the authors extended their investigation to human HCC specimens to evaluate the prognostic relevance of the MET-SP1-TRIB3-FOXO1 axis. Immunohistochemistry analysis of the Tongji HCC cohort (n=75) revealed a significant positive correlation between TRIB3, MET, and SP1 expression, and a strong inverse relationship between these markers and FOXO1 levels. These findings suggest that TRIB3 not only acts as a functional mediator but also bridges MET signaling and FOXO1 suppression in human HCC. Importantly, high TRIB3 expression, especially when combined with elevated MET or SP1 and reduced FOXO1, was associated with significantly worse overall survival (OS) and recurrence-free survival (RFS). Multimarker stratification analyses further underscored the prognostic value of integrating these markers, with the worst clinical outcomes observed in patients harboring high MET or SP1 and TRIB3 levels alongside low FOXO1 expression. These results not only validate the biological relevance of the axis in human tumors but also highlight its potential utility in risk stratification and therapeutic decision-making. Future studies in larger, independent cohorts are warranted to confirm these findings and assess their translational applicability.
While TRIB3 has previously been implicated in multiple cancer types [
7], by integrating transcriptomic, proteomic, molecular, and functional analyses, this study comprehensively not only identifies TRIB3 as a novel effector downstream of MET but also establishes the MET-ERK-SP1-TRIB3-COP1-FOXO1 cascade as a critical driver of HCC progression. Moreover, the use of liver-directed gene therapy, such as AAV8-shTRIB3, highlights the feasibility of disrupting oncogenic circuits in HCC through innovative therapeutic strategies.
Looking forward, the development of TRIB3-specific inhibitors or strategies to stabilize FOXO1 may offer more effective options for patients with MET-dysregulated HCC. Future investigations should also assess the role of TRIB3 in resistance to immune checkpoint inhibitors which may open avenues for rational combination therapies in HCC.
In conclusion, Wang et al. have elegantly delineated a comprehensive molecular cascade through which MET drives hepatocarcinogenesis. Targeting MET-ERK-SP1-TRIB3-COP1-FOXO1 axis represents a promising therapeutic approach to overcome the limitations of direct MET inhibitors and improve outcomes for patients with advanced HCC.
FOOTNOTES
-
Authors’ contribution
J.E.H., S.S.K., and J.W.E. drafted the manuscript, while J.Y.C. and J.W.E. supervised and approved the final version of the manuscript.
-
Acknowledgements
This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number HR21C1003), and by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT), Republic of Korea (grant numbers RS-2022-NR070489).
-
Conflicts of Interest
The authors have no conflicts of interest to declare.
Abbreviations
Gene set enrichment analysis
hydrodynamic tail vein injection
mitogen-activated protein kinase
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Citations
Citations to this article as recorded by
- Correspondence to Editorial 2 on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation”
Tiantian Wang, Wenjie Huang, Limin Xia
Clinical and Molecular Hepatology.2026; 32(1): e93. CrossRef - Reply to correspondence 2 on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation”
Ji Eun Han, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e121. CrossRef
