A SIRT1-PERK-HSPA5-MARCHF1 Proteostasis Axis Controls GPX4 Stability and Ferroptotic Susceptibility in Hepatic Stellate Cells.

Authors

Yixiao Wang, Huiya Ying, Hangu Wang, Jun Xu, Dandan Zhu, Hong Pan, Yuan Zeng, Xiangting Zhang, Ziqiang Xia, Ruoru Zhou, Xingyue Yu, Xiao Wu, Weimin Cai, Qian Zhao, Fujun Yu

Published in

Antioxidants & redox signaling. Pages 15230864261495029. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

Liver fibrosis is a chronic inflammatory condition characterized by excessive extracellular matrix accumulation driven by hepatic stellate cell (HSC) activation, and inducing HSC ferroptosis represents an effective strategy to restrain fibrogenesis. In this study, liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of CCl₄ (10% in oil) twice weekly, and nodosin (1, 5, or 10 mg/kg/day) was administered by gavage starting 2 weeks after CCl₄ administration. This study aimed to evaluate the anti-fibrotic efficacy of nodosin, an ent-kaurane diterpenoid derived from the traditional Chinese medicinal herb Isodon serra, and investigate its mechanisms in CCl₄-induced liver fibrosis.
Our findings demonstrated that nodosin promotes HSC ferroptosis by regulating protein kinase R-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent glutathione peroxidase 4 (GPX4) proteostasis. Nodosin-mediated suppression of ATF4 reduced heat shock protein family A member 5 (HSPA5) expression, thereby enhancing the MARCHF1-GPX4 interaction and promoting K48-linked polyubiquitination and proteasomal degradation of GPX4. Mechanistically, HSPA5 restricted MARCHF1 access to GPX4, and K191 was identified as a functionally relevant ubiquitination site of GPX4. Nodosin also promoted SIRT1-mediated deacetylation of PERK at K1101, providing further mechanistic support for the regulation of PERK/ATF4 signaling.
This study identifies a previously unrecognized endoplasmic reticulum stress-proteostasis-ferroptosis regulatory axis in HSCs. We demonstrate that HSPA5 constrains MARCHF1-dependent K48 ubiquitination and degradation of GPX4, establishing GPX4 proteostasis as a key determinant of ferroptotic susceptibility during liver fibrogenesis. Nodosin modulates this axis through SIRT1-PERK signaling.
Overall, nodosin alleviated CCl₄-induced liver fibrosis by promoting HSC ferroptosis. These findings reveal a proteostatic mechanism linking ER stress to GPX4 stability and ferroptotic susceptibility in HSCs. Antioxid. Redox Signal. 00, 000-000.

PMID:
42844220
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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