Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disorders worldwide, encompassing a continuous pathological spectrum ranging from simple steatosis and alcoholic steatohepatitis to hepatic fibrosis, cirrhosis and hepatocellular carcinoma [
1]. In recent years, the global incidence of ALD has been steadily increasing, and it has become the principal indication for liver transplantation in western countries [
2]. Although significant progress has been achieved in both clinical and basic research, there is still no approved pharmacotherapy with proven efficacy for the treatment of ALD [
3]. This situation highlights the urgent need for comprehensive and multilevel strategies, including early diagnosis and stratified management at the clinical level, and molecular pathogenesis studies at the mechanistic level, to identify promising therapeutic targets, and accelerate the development of novel pharmacological interventions.
Among the key pathogenic drivers of ALD, endoplasmic reticulum (ER) stress has emerged as a central mechanism linking oxidative injury, lipid toxicity, and metabolic dysfunction [
4]. Ethanol metabolism yields acetaldehyde and reactive oxygen species, which impair ER homeostasis and elicit stress signaling via the canonical protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1α), and activating transcription factor 6 (ATF6) pathways [
5]. Notably, inhibition of these sensors does not fully suppress downstream events such as ATF4 activation in ALD, implying the involvement of non-canonical ER stress pathways [
6]. Defining these alternative mechanisms and their interplay is key to uncovering the pathogenic basis of ALD and to developing novel therapeutic strategies.
In the latest issue of
Clinical and Molecular Hepatology, Liu et al. [
7] comprehensively delineate a novel mechanism by which the RAB25-GCN1 signaling axis induces non-canonical ER stress in ALD. By integrating single-cell transcriptomic profiling with analyses of liver tissues from ALD patients, as well as complementary animal and cellular models, the authors systematically demonstrate that RAB25 plays a pivotal role in linking chronic ethanol exposure to sustained ER stress and liver injury. Clinically, the small GTPase RAB25 was upregulated in the liver of ALD patients, with expression levels positively correlating with both disease severity and the abundance of key ER-stress markers. Immunofluorescence analyses further revealed markedly enhanced co-localization of RAB25 with ATF4 in hepatocytes, suggesting that RAB25 may directly participate in the activation and amplification of stress signaling. Mechanistically, the authors demonstrated that RAB25 interaction with GCN1 blocks its K33-linked ubiquitination and degradation, which in turn promotes GCN2 phosphorylation and triggers ATF4-mediated ER stress signaling. Functional studies showed that RAB25 knockout significantly alleviated hepatic steatosis and inflammation in ethanol fed mice. Importantly, this study provides the first compelling evidence that RAB25 is selectively upregulated in ALD in both experimental models and patient samples, while remaining unchanged in other hepatic disorders. This ethanol‑specific pattern underscores the unique regulatory nature of RAB25 and provides valuable mechanistic insight into how ethanol‑induced hepatic injury engages distinctive stress‑response pathways that set it apart from other liver diseases. By defining a RAB25-GCN1-ATF4 non‑canonical ER stress axis, Liu et al. [
7] further uncover a novel molecular basis for persistent ER stress and hepatocellular injury induced by chronic alcohol exposure. Collectively, these findings establish a conceptual framework that links RAB25‑mediated signaling with the pathogenesis of ALD.
While this study is methodologically rigorous and conceptually innovative, several aspects warrant further consideration. First, the authors propose that hypoxia-inducible factor 1-alpha (HIF1A) acts as an upstream transcriptional regulator of RAB25 [
7]. This hypothesis is biologically plausible and supported by transcriptional correlation and co-expression analyses. However, direct mechanistic evidence such as promoter binding or reporter assays remains lacking. Notably, previous investigations indicate that HIF1A exerts a hepatoprotective role in ethanol‑induced steatosis by activating DEC1, a downstream transcriptional repressor regulated by HIF1A [
8]. Functional validation will therefore be essential to establish a causal regulatory relationship between HIF1A and RAB25 [
7]. Furthermore, HIF1A is widely activated in various liver disorders, including metabolic dysfunction-associated steatotic liver disease, fibrosis, and ALD [
9], yet RAB25 upregulation appears confined to ALD [
7]. This discrepancy suggests that ethanol-specific metabolic or biophysical disturbances may underlie RAB25 activation. Ethanol metabolism, in particular, is known to alter membrane fluidity and reorganize lipid raft architecture [
10]. These ethanol‑induced changes may selectively facilitate the activation or recruitment of membrane-associated small GTPases such as RAB25, providing a plausible explanation for its disease-specific induction pattern. Consistent with this notion, RAB25 deficiency markedly attenuated ethanol-induced ER stress and liver injury but exerted no comparable effect in other models of hepatic injury. This observation reinforces the view that RAB25 functions in an etiology-specific manner, reflecting selective engagement under ethanol-induced membrane or metabolic stress rather than a general role in ER homeostasis. Future investigations should thus clarify the upstream conditions that selectively engage RAB25, define the structural basis linking ethanol metabolism to RAB25 activation. Second, RAB25 is a multifunctional small GTPase that is broadly expressed in epithelial tissues such as the skin, tongue, kidney, and stomach [
11,
12]. Consequently, its tissue-specific roles and possible systemic side effects should be carefully assessed before contemplating therapeutic targeting. Future efforts focusing on hepatocyte-restricted modulation of RAB25 may help translate these mechanistic findings into clinically applicable strategies.
Despite these limitations, Liu et al. [
7] conducted a comprehensive study that integrated clinical validation with mechanistic innovation. By combining patient samples with multiple experimental models, the authors systematically delineated the pathogenic role of RAB25 in ALD, showing that it promotes disease progression through activation of the ER stress pathway and sustained ATF4 signaling. The study further demonstrates that hepatic RAB25 deficiency alleviates ethanol-induced liver injury, likely by preserving mitochondrial function, reducing lipogenesis, and attenuating inflammatory responses. Collectively, this work provides new mechanistic insight into non-canonical ER stress signaling and its contribution to ALD progression, while expanding our understanding of the role of the RAB25-GCN1 axis within the hepatic stress network. Although certain mechanistic aspects remain to be refined and validated, the study represents a significant advance in elucidating the molecular pathology of ALD and highlights RAB25 as a potential therapeutic target for the prevention and treatment of ALD.
FOOTNOTES
-
Authors’ contribution
M.W. and Q.C. drafted the manuscript. L.Z. and H.W. revised the manuscript.
-
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 82530022).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
alcohol-associated liver disease
activating transcription factor 6
hypoxia-inducible factor 1-alpha
inositol-requiring enzyme 1 alpha
protein kinase RNA-like endoplasmic reticulum kinase
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Citations
Citations to this article as recorded by
- RAB25 as a liver-selective modulator of endoplasmic reticulum stress in alcohol-associated liver disease: Correspondence to editorial on “RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression”
Zi-Bin Zhan, Xue-Wen Liu, Ze-Hua Li, Fan-Hong Zeng, Kun-Hao Bai, Jun Weng
Clinical and Molecular Hepatology.2026; 32(3): e354. CrossRef
