Cholesterol gallstone disease (CGS) is one of the most prevalent gastrointestinal conditions, affecting up to 20% of adults worldwide [1]. This bile disorder, caused by cholesterol supersaturation, can result in severe complications such as cholecystitis, cholangitis, and biliary pancreatitis. In the United States alone, more than 700,000 cholecystectomies are performed annually, underscoring the substantial burden CGS places on patients and healthcare systems [1,2]. At the molecular level, CGS pathogenesis centers around the ATP-binding cassette subfamily G members 5 and 8 (ABCG5/ABCG8), which play essential roles in cholesterol transport into bile and maintaining bile composition [3]. Dysfunction of ABCG5/ABCG8 disrupts cholesterol efflux and leads to bile supersaturation, ultimately resulting in gallstone formation [3].

Recent research highlights the strong association between CGS and metabolic dysfunction-associated steatotic liver disease (MASLD), particularly its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). MASH is marked by chronic liver inflammation and fibrosis, often linked to metabolic syndrome and type 2 diabetes mellitus [4,5]. These pathological changes impair bile acid synthesis and secretion, disrupting bile homeostasis and exacerbating CGS risk [6,7]. Furthermore, the interplay between cholesterol metabolism and inflammatory signaling in MASLD accelerates CGS progression, underlining the positive correlation of liver and biliary pathologies [8]. However, the precise molecular mechanisms linking MASH and CGS still remain poorly defined [9]. Recent studies have suggested that Golgi membrane protein 1 (GOLM1) may act as a key regulator in the pathological progression of MASH and CGS. Suppression of GOLM1 has been shown to cause intracellular accumulation of cholesteryl esters, highlighting its role in regulating cholesterol efflux [10,11]. Furthermore, GOLM1 expression is closely associated with major pathological features of MASH, such as hepatic inflammation and fibrosis [12,13]. Inflammatory cytokines, including interleukin-1β (IL-1β), have been recognized as important regulators of GOLM1 expression [13,14], further supporting the role of GOLM1 in the interaction between hepatic inflammatory responses and cholesterol metabolism. These findings suggest that GOLM1 plays an important role in coordinating the pathological mechanisms involved in both MASH and CGS.

In the latest issue of Clinical and Molecular Hepatology, Li et al. [15] present an in-depth investigation into the molecular mechanisms of GOLM1-OPN-ABCG5 axis during pathogenesis of MASH and CGS. The authors leveraged UK Biobank data to examine the molecular association between MASH and gallstone formation. The authors reported a significantly higher prevalence of gallstones in MASH patients compared to those with simple steatosis or healthy controls. These findings suggested a potential association between MASH and gallstone formation, distinct from simple steatosis, and underscored the need for mechanistic studies exploring cholesterol-bile metabolism in MASH-mediated gallstone formation. Using a high-fat diet (HFD)-induced MASH mouse model, the authors demonstrated fundamental roles of GOLM1 in gallstone formation. MASH mice exhibited increased GOLM1 expression, elevated levels of pro-inflammatory cytokines (IL-1β, IL-6), and a gallstone formation rate of 75%. Conversely, GOLM1-knockout (GOLM1−/−) mice showed a dramatic reduction in gallstone formation (16.7%), accompanied by lower bile cholesterol levels and decreased gene expression of ABCG5. These findings highlighted the significant role of GOLM1 in regulating ABCG5 gene expression, contributing to bile cholesterol homeostasis and mitigating gallstone formation.

Further experiments revealed that GOLM1 overexpression increased ABCG5 levels and bile cholesterol, underscoring its bidirectional role in the regulation of bile composition. The authors found that osteopontin (OPN) is a critical mediator in the GOLM1-ABCG5 axis. As consistent, GOLM1-knockout mice exhibited significant reduction of OPN gene expression while GOLM1 overexpression positively correlated with elevated OPN levels. Functional analyses demonstrated that OPN deficiency decreased ABCG5 expression and bile cholesterol, while OPN overexpression reversed these effects. Notably, OPN overexpression partially restored ABCG5 levels and bile cholesterol in GOLM1-deficient models, highlighting OPN as an important factor in the GOLM1-ABCG5 axis for bile cholesterol modulation. Under inflammatory conditions, GOLM1 translocates to the nucleus, where it binds directly to a specific region (-267 to -127) of the OPN promoter to activate transcription. Activated OPN stabilized ABCG5/ABCG8, maintaining bile composition and preventing gallstone formation. The authors further demonstrated that IL-1β-driven inflammation enhanced the GOLM1-OPN-ABCG5 axis, linking inflammatory pathways to dysregulated bile metabolism. These findings build on prior studies demonstrating GOLM1’s role in regulating inflammatory cytokines and contributing to bile metabolism disorders (Fig. 1) [13,14,16].

Analysis of liver tissue samples from MASH patients revealed significantly elevated IL-1β, GOLM1, OPN, and ABCG5 expression in patients with gallstones compared to those without, despite similar hepatic cholesterol levels. These findings suggest that inflammatory and metabolic factors are central to gallstone formation in the context of MASH. This study suggests the GOLM1-OPN-ABCG5 axis as a critical pathway linking pathogenic progression of MASH and CGS, providing a robust foundation for therapeutic development. Future studies should evaluate whether GOLM1 inhibition affects alternative bile acid synthesis pathways, such as CYP27A1 and CYP7B1 [17]. These alternative bile acid synthesis pathways may undermine the efficacy of GOLM1-targeted therapies, necessitating comprehensive evaluations to ensure their stability and effectiveness. The impact of GOLM1 inhibition on bile acid metabolism and gut microbiota should be thoroughly investigated, as changes in the bile acid pool may alter systemic metabolism and immune responses [18]. Exploring the potential for combination of GOLM1 inhibitors with FXR agonists or MASLD treatments, including PPAR-γ agonists and FGF21 analogs, offers promising therapeutic opportunities [19]. FXR is a key regulator of bile acid metabolism and inflammation, thus GOLM1 inhibition could synergistically enhance therapeutic outcomes with FXR agonists [18].

In conclusion, the GOLM1-OPN-ABCG5 axis plays a pivotal role in linking inflammation and metabolism, highlighting GOLM1 as a potential therapeutic target for treating CGS in MASH patients. Comprehensive research will pave the way for personalized GOLM1-based therapies, revolutionizing the treatment of metabolic liver diseases and related metabolic disorders.