We sincerely thank Dr. Nahee Hwang and Sungsoon Fang for acknowledging our recent work “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” [1,2]. Metabolic dysfunction-associated steatohepatitis (MASH) and cholesterol gallstones (CGS) are common digestive diseases, with MASH linked to the onset of CGS [2,3]. However, the mechanism linking these conditions remains unclear. Golgi membrane protein 1 (GOLM1) is notably upregulated in MASH patient livers and is involved in cholesterol metabolism [2]. GOLM1 can translocate to the nucleus of liver cells and activate osteopontin (OPN) transcription, thereby increasing ATP-binding cassette subfamily G member 5 (ABCG5)-mediated cholesterol efflux [2]. Interleukin-1β (IL-1β), a key proinflammatory factor in MASH, increases the expression of GOLM1 and promotes its nuclear translocation [2]. Thus, the GOLM1-OPN-ABCG5 axis may connect liver inflammation to cholesterol metabolism and play a crucial role in metabolic diseases, including MASH-related CGS. Notably, as the Editorial noted, bile acid synthesis, similar to cholesterol metabolism, is disrupted in MASH and contributes to various metabolic diseases. The potential interaction between GOLM1 and bile acid metabolism, along with the prospective application of related inhibitors in combination, merits further investigation.

Bile acid metabolism, a critical physiological process, plays a pivotal role in regulating energy utilization, drug metabolism, and immune responses, and it is also implicated in the progression of metabolic diseases [4-6]. This metabolic pathway is influenced by various enzymes, notably cytochrome P450 family 7 subfamily A member 1 (CYP7A1), cytochrome P450 family 7 subfamily B member 1 (CYP7B1), and cytochrome P450 family 27 subfamily A member 1 (CYP27A1), which serve as rate-limiting enzymes in bile acid synthesis and have attracted considerable scholarly attention [7]. In our in vivo experiments, the effect of GOLM1 knockdown on CYP7A1 expression was not significant, suggesting that GOLM1 may not affect classic bile acid synthesis. However, the role of GOLM1 in alternative bile acid synthesis is unclear. As the critical rate-limiting enzymes in alternative bile acid synthesis, CYP7B1 and CYP27A1 are closely linked to the formation of CGSs and the advancement of MASH [8,9]. Consequently, GOLM1 has the potential to interact with CYP7B1 and CYP27A1. Research suggests that deoxycholic acid upregulates GOLM1 expression via the NF-κB pathway, possibly involving CYP7B1 and CYP27A1 in GOLM1 regulation [10]. However, it remains uncertain whether GOLM1 influences bile acid synthesis by modulating the expression of CYP7B1 or CYP27A1. The expression of CYP7B1 and CYP27A1 can be regulated by the farnesoid X receptor (FXR), a nuclear receptor that interacts with transcription factors to exert transcriptional regulatory effects [7]. GOLM1 has been observed to translocate into the cell nucleus and participate in transcriptional regulation [2]. Based on this observation, we propose that GOLM1 may interact with FXR in the nucleus to regulate bile acid synthesis. However, additional research is needed to substantiate this hypothesis.

Recent research has revealed a significant association between bile acid species and immune efficacy [11]. Specifically, lithocholic acid has been shown to suppress T-cell function by modulating endoplasmic reticulum stress, whereas ursodeoxycholic acid can counteract this effect [11]. The established relationship between immunity and metabolic disorders prompted the investigation of whether GOLM1 could modulate immune responses through bile acid metabolism, thereby contributing to the progression of CGSs and MASH [12,13]. The interaction between the gut microbiota and the bile acid metabolic network is pivotal in the pathogenesis of various diseases, including metabolic disorders, inflammatory conditions, and cancer [14]. Numerous therapeutic agents that target bile acid metabolism, as well as probiotic formulations, have been developed. For example, FXR agonists promote weight loss and mitigate metabolic syndrome in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), whereas Lactobacillus reuteri NCIMB 30242 has anti-inflammatory and cholesterol-lowering properties [14]. In addition to its potential role in bile acid metabolism, a recent study reported that GOLM1 may also influence the abundance of various microbes, such as Methyloversatilis discipulorum [15]. Therefore, the integration of GOLM1 inhibitors with FXR agonists or probiotics represents a promising strategy for synergistically improving therapeutic outcomes. Nonetheless, additional fundamental and clinical research is necessary to ascertain the specific diseases that GOLM1 inhibitors may effectively treat and to evaluate their potential to increase treatment efficacy.