Dear Editor,
We acknowledge the authors’ considered response [
1] to our editorial on recent work [
2] that identifies a non-canonical RAB25–GCN1 signaling axis promoting endoplasmic reticulum (ER) stress and offering new mechanistic insight into alcohol-mediated hepatic homeostasis [
3]. We sincerely thank the authors for their thoughtful and comprehensive correspondence in response to our editorial commentary on their recent study published in
Clinical and Molecular Hepatology. We support the view that investigating the non-canonical RAB25–GCN1 axis underlying ER stress–driven liver injury is essential for elucidating the pathogenesis of alcohol-associated liver disease (ALD). The authors provide a persuasive elaboration of their findings, supporting the concept that the non-canonical RAB25–GCN1 signaling axis operates independently of classical unfolded protein response sensors to shape hepatocellular stress responses. Their additional clarification regarding the ER-enriched localization of RAB25, validated through single-cell sequencing and histology, strengthens the notion that intracellular trafficking pathways are not merely passive bystanders but active participants in the progression of ALD. The Gene Set Enrichment Analysis further supports this by demonstrating a robust correlation between high RAB25 expression and signatures of ER lumen stress and the unfolded protein response.
We also appreciate the authors’ insightful discussion of the RAB25-dependent stabilization of GCN1, which suppresses its K33-linked ubiquitination and degradation, thereby sustaining GCN2 activation and driving downstream ATF4-dependent ER stress signaling. This finding is particularly significant as it suggests a metabolic plasticity where the source of eIF2α phosphorylation—whether via PERK or GCN2—is governed by the specific subcellular origin of the metabolic stress. Such a mechanism-based heterogeneity may account for the distinct cellular responses observed across the liver lobule during chronic alcohol exposure. The correspondence further highlights the pathological importance of impaired inter-organelle communication, specifically the dysregulated interactions between the ER and mitochondria. The authors’ evidence that RAB25 suppression preserves mitochondrial morphology and oxidative phosphorylation capacity suggests that RAB25 acts as a central modulator coordinating organellar dysfunction. By facilitating uncontrolled calcium flux from the ER to the mitochondria, RAB25 likely triggers the mitochondrial permeability transition and excessive ROS generation, which are hallmarks of metabolic failure in ALD. In addition, RAB25 promotes CXCL12 induction through the ER stress–NLRP3 axis, as suppression of RAB25 attenuates NLRP3 expression and caspase-1 activation. Within this framework, the RAB25–GCN1 axis is closely linked to ER stress–NLRP3 inflammatory signaling, providing a mechanistic basis for RAB25-mediated CXCL12 expression and subsequent immune cell recruitment. Together, these findings position RAB25 as a critical amplifier of hepatocyte-driven inflammation by linking ER stress to NLRP3 activation and CXCL12-mediated inflammatory signaling in ALD.
In conclusion, this correspondence reframes the conceptual framework of ALD by demonstrating that elevated RAB25 accelerates ER stress through a ubiquitination-dependent mechanism. This finding challenges the conventional view of ALD as a disorder driven predominantly by oxidative injury, lipid peroxidation, and inflammation [
4], and instead positions defective inter-organelle communication as a central pathogenic feature. By defining the RAB25–GCN1–GCN2–ATF4 axis as a key mediator of noncanonical ER stress, this work provides a new framework for understanding hepatocyte vulnerability to metabolic injury. Moreover, the identification of RAB25 as an integrative molecular node that bridges ER signaling, mitochondrial dysfunction, and immune activation aligns with emerging paradigms emphasizing organelle crosstalk as a fundamental basis of metabolic homeostasis. Collectively, these findings expand the pathogenic and therapeutic landscape of ALD and emphasize the importance of interrogating coordinated cellular stress networks. We appreciate the authors’ engagement and agree that elucidation of noncanonical ER stress pathways, exemplified by the non-canonical RAB25–GCN1 axis, will be essential for advancing therapeutic strategies for ALD.
FOOTNOTES
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Authors’ contributions
Seol Hee Park: Writing draft. Wonhyo Seo: Conceptualization, critical revision of the manuscript and supervision.
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Acknowledgements
This study was supported by the National Research Foundation of Korea (2021R1A6C101A442, 2022R1C1 C1008912, RS-2023-00262969), the Supporting Program of The Korean Association for the Study of the Liver and the Korean Liver Foundation, and the Research Support Project for Young Medical Scientists funded by the Daewoong Foundation.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
alcohol-associated liver disease
REFERENCES
- 1. Liu XW, Zhan ZB, Gong Y, Li ZH, Bai KH, Weng J. Correspondence to editorial on “RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression”. Clin Mol Hepatol 2026;32:e349-e353.
- 2. Park SH, Seo W. Mechanistic insights into a noncanonical RAB25-GCN1 axis in ALD: Editorial on “RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression”. Clin Mol Hepatol 2026;32:1390-1393.
- 3. Liu XW, Zhan ZB, Li ZH, Zhang Y, Qiao XY, Li XM, et al. RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression. Clin Mol Hepatol 2026;32:200-220.
- 4. Kang J, Park SH, Khanam M, Park SB, Shin S, Seo W. Impact of binge drinking on alcoholic liver disease. Arch Pharm Res 2025;48:212-223.
Citations
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