What question did this study set out to answer?

This research aims to clarify how UBQLN1 contributes to liver fibrosis related to metabolic dysfunction, focusing on extracellular vesicles.

March 12, 2026

Lipotoxic hepatocyte-derived UBQLN1 -enriched small extracellular vesicles activate hepatic stellate cells to promote hepatic fibrosis

Key Points

This research aims to clarify how UBQLN1 contributes to liver fibrosis related to metabolic dysfunction, focusing on extracellular vesicles.
Analyzed serum and serum-derived small extracellular vesicles from MASH patients.
Used multicenter cohort data with 150 participants to assess UBQLN1 levels.
Investigated mechanisms of UBQLN1 regulation in hepatocytes through O-GlcNAcylation and phosphorylation.
Conducted experiments in mouse models and human liver organoids to examine functional effects.
Significantly elevated UBQLN1 levels were detected in MASH patients' serum and serum-derived sEVs.
Diagnostic accuracies of UBQLN1 were 0.89 for serum and 0.95 for serum-derived sEVs.
Lipotoxic stress increased UBQLN1 levels via regulatory mechanisms affecting its degradation.
Hepatocyte-derived sEVs containing UBQLN1 promoted hepatic stellate cell activation, leading to fibrosis.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) serves as a primary contributor to liver fibrosis, cirrhosis, and hepatocellular carcinoma, yet specific diagnostic markers and therapeutic targets remain unavailable. This study elucidates the molecular mechanism by which UBQLN1 (ubiquilin 1) promotes MASH-related liver fibrosis by regulating small extracellular vesicles (sEVs) secretion and the functionality of the lysosome-mitochondria axis, as well as its clinical significance. Analysis of a multicenter cohort (n = 150) demonstrated significantly elevated UBQLN1 levels in both serum and serum-derived sEV from MASH patients, exhibiting diagnostic accuracies of 0.89 and 0.95, respectively. Furthermore, increased UBQLN1 was observed in mouse models of MASH, hiPSCs-derived human liver organoids, and oleic acid and palmitic acid injured hepatocytes (lipotoxic hepatocytes). Mechanistically, lipotoxic stress induces O-GlcNAcylation at the T277 site of UBQLN1 via OGT (O-GlcNAc transferase), which competitively inhibits its phosphorylation, consequently reducing ubiquitin-mediated degradation. Hepatocyte UBQLN1 facilitates the secretion of sEVs by regulating LAMP1-mediated fusion of multivesicular bodies (MVBs) with lysosomes. Subsequently, sEVs containing UBQLN1 regulate the activation of hepatic stellate cells by degrading the V-ATPase subunit ATP6V1B2 through E54D-dependent ubiquitin ligase activity, thereby inhibiting lysosomal acidification and mitophagy. Moreover, hepatic-specific knockdown of Ubqln1 or hepatocyte-specific knockdown of Ogt significantly alleviates fibrosis and metabolic disorders in MASH mice. This study elucidates the critical role of the post-translational modification regulatory network of UBQLN1 in the progression of MASH and proposes its translational potential as an integrated therapeutic target, providing a theoretical basis for the development of sEV-based intervention strategies.

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Cite This Study

YANG et al. (Sun,) studied this question.

synapsesocial.com/papers/69b2573196eeacc4fcec5caf https://doi.org/https://doi.org/10.1080/15548627.2026.2642976

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