Dear Editor,
We sincerely thank Dr. Li Zuo and Dr. Wang Hua for their insightful editorial commenting on our recent publication, “
RAB25/GCN1 signaling promotes ER stress to mediate alcohol-associated liver disease progression,” published in
Clinical and Molecular Hepatology [
1]. Their discussion highlights the concept of ethanol-specific stress responses and provides important perspectives on the mechanistic complexity of alcohol-associated liver disease (ALD) [
2].
ALD represents one of the most common chronic liver conditions and has become a leading contributor to global liver disease incidence and mortality in recent years [
3-
5]. Chronic ethanol exposure increases hepatic oxygen demand and creates a hypoxic microenvironment, particularly in pericentral regions of the liver lobule. Hypoxia-inducible factor 1 (HIF-1) is a central mediator of cellular adaptation to hypoxia. Upon stabilization, HIF-1α dimerizes with HIF-1β, translocates to the nucleus, and regulates the transcription of hypoxia-responsive genes [
6]. Accumulating evidence indicates that HIF-1α plays context-dependent roles in ALD pathogenesis. While HIF-1α deficiency aggravates alcohol-induced hyperlipidemia and steatosis through DEC1 regulation, suggesting a protective role in early disease stages [
7], HIF-1α also contributes to later disease progression by promoting angiogenesis, modulating gut–liver axis dysfunction, and regulating mitochondrial oxidative stress [
8-
10].
Importantly, HIF-1α signaling intersects with endoplasmic reticulum (ER) stress pathways. Previous studies have shown that HIF-1α activation can induce ER stress and CHOP-mediated apoptosis [
9]. Consistent with these findings, our recent study demonstrated that HIF-1α activation mediates ER stress in ALD [
1]. Notably, we observed a strong co-expression of RAB25 with HIF-1α (
Fig. 1A,
1B). In silico analysis using the JASPAR database identified two putative HIF-1α binding sites within the RAB25 promoter region (MA_1106.01;
Fig. 1C), suggesting that RAB25 may represent a downstream transcriptional target of HIF-1α and function as a modulatory node linking hypoxic signaling to ER stress activation in ALD. Although the precise regulatory domains and molecular interactions between HIF-1α and RAB25 remain to be elucidated, further characterization of the HIF-1α–RAB25–ER stress axis may help clarify the dual and context-dependent roles of HIF-1α in ALD progression.
Given that alcohol consumption represents a major global contributor to morbidity and mortality, particularly as a primary driver of advanced liver disease [
10], there remains a compelling need for evidence-based therapeutic strategies to mitigate alcohol-related harm [
4]. Across all stages of ALD, sustained alcohol abstinence remains the cornerstone of clinical management [
4]. In advanced disease, additional interventions—including early liver transplantation and mechanism-informed pharmacotherapies such as IL-1β inhibitors [
11] and antioxidants like N-acetylcysteine [
4]—constitute important therapeutic options.
Within this therapeutic landscape, the editorial’s proposal to develop RAB25-targeted interventions for ALD is both timely and clinically relevant, while also raising important considerations regarding target specificity and translational feasibility. Although RAB25 is predominantly expressed in extrahepatic epithelial tissues, including the stomach, skin, and kidneys [
12], its induction in the context of ALD appears to be highly liver-selective. In our tissue-specific analysis following chronic alcohol exposure, RAB25 expression was not significantly upregulated in the kidney, lung, ovary, testis, heart muscle, cerebral cortex, or colon (
Fig. 1D). These findings indicate that RAB25 induction during ALD progression is largely restricted to hepatic tissue. This liver-specific pattern is further supported by our previous observation that RAB25 expression remains unchanged in other liver diseases, underscoring its specificity to ALD pathogenesis [
1].
In summary, our findings demonstrate that alcohol-induced upregulation of hepatic RAB25 drives activation of the ER stress pathway and sustained ATF4 signaling, thereby contributing directly to the pathogenesis of alcohol-associated liver disease. We identify RAB25 as a key molecular link connecting ER stress signaling to ALD progression. The editorial’s perspective highlighting the translational potential of targeting RAB25 in ALD is both timely and forward-looking. We further agree with the emphasis on defining the causal relationship between hypoxia-inducible factor 1α (HIF-1α) and RAB25 in this setting. Given the pleiotropic roles of HIF-1α in hepatic lipid metabolism and injury responses, elucidating its regulatory interaction with RAB25 may help explain the disease-specific induction of RAB25 in ALD. Ongoing studies in our laboratory are focused on dissecting this regulatory axis, with the aim of advancing mechanistic insight and informing future therapeutic strategies for alcohol-associated liver disease.
FOOTNOTES
-
Authors’ contribution
Manuscript drafting: Zi-bin Zhan. Manuscript revision and final approval: all authors.
-
Acknowledgements
This work was funded by the National Natural Science Foundation of China (Grant No. 82200703).
We thank Dr. Li Zuo and Dr. Wang Hua for their insightful and constructive comments.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1.RAB25 expression is associated with hypoxia-inducible factor 1α (HIF-1α) signaling and exhibits liver-selective induction in alcohol- associated liver disease. (A) Feature plots showing the expression of RAB25 and HIF-1α in representative hepatocytes, with coexpression indicated. (B) Gene set enrichment analysis (GSEA) of HIF-1α–associated signaling pathways. The enrichment plot illustrates pathways significantly enriched in the RAB25 high-expression group. A normalized enrichment score (NES) >1 with nominal P<0.05 was considered statistically significant. (C) Schematic representation of putative HIF-1α-binding sites (HBS) within the genomic region adjacent to the transcription start site (TSS) of the RAB25 gene. (D) Extrahepatic tissue sections from pair-fed and ethanol-fed mice were subjected to hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) analysis for RAB25 expression. No significant elevation of RAB25 was observed in non-hepatic tissues. Scale bars, 100 μm.
Abbreviations
alcohol-associated liver disease
hypoxia-inducible factor 1
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