The recent publication of “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” in Clinical and Molecular Hepatology provides valuable insights into the molecular mechanisms underlying cholesterol gallstone (CGS) formation in metabolic dysfunction-associated steatohepatitis (MASH) [1]. In response, we authored the editorial “Unraveling the role of GOLM1-OPN-ABCG5 axis in MASH” [2]. Drs. Yi-Tong Li, WeiQing Shao, Zhen-Mei Chen, Jing Lin, and Jin-Hong Chen subsequently provided a detailed response to our editorial [3]. We appreciate their comprehensive discussion and response to the points raised in our editorial; we look forward to further constructive discourse regarding their findings.

The identification of molecular targets in MASH remains a critical issue within biomedical research [4-7]. Li et al. provided a very interesting discussion offering significant understanding of the mechanistic relationship between MASH and the formation of CGS [1]. As emphasized in their correspondence, sex-related factors, particularly estrogen, may influence the development of MASH and CGS [3]. We agree that further investigation into the precise role of estrogen in MASH-related CGS formation is essential for a more comprehensive understanding of the underlying mechanisms. Several studies have demonstrated the influence of estrogen on gallstone formation, highlighting the involvement of estrogen receptor GPR30 in promoting additional lithogenic effects. This receptor functions independently of ERα, thereby facilitating cholesterol cholelithogenesis in female mice [8-10]. Considering the complexity of these interactions, we expect that future studies concerning the impact of sexrelated factors on MASH pathophysiology will provide valuable insights, contributing to the development of more effective and sex-specific therapeutic strategies. We also agree with the authors’ assertion that a tissue-specific knockout system (e.g., liver, adipose tissue) would effectively address a key research gap, particularly given the relationship between MASH livers and Golgi membrane protein 1 (GOLM1) expression levels. A previous study by Shen et al. [11] revealed elevated serum GOLM1 levels in patients with osteoporosis and increased GOLM1 expression in bone marrow mesenchymal stem cells (i.e., progenitors of adipocytes, chondrocytes, and osteoblasts) in an ovariectomy-induced osteoporosis mouse model. These findings suggest that GOLM1 is involved in various pathophysiological processes; further studies are warranted to investigate its potential as a therapeutic target in these conditions.

In summary, increasing evidence links GOLM1 to multiple pathophysiological processes, underscoring its potential as both a biomarker and a therapeutic target. Further investigation of GOLM1 is expected to enhance its clinical applicability and improve disease management and treatment outcomes for patients with MASH.