{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:34:36Z","timestamp":1792787676530,"version":"4.5.0"},"reference-count":35,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Medical Science and Technology Project of Zhejiang Province","award":["No. 2024KY1264"],"award-info":[{"award-number":["No. 2024KY1264"]}]},{"name":"Wenzhou Municipal Science and Technology Bureau","award":["No. Y20220024"],"award-info":[{"award-number":["No. Y20220024"]}],"id":[{"id":"https:\/\/ror.org\/02fr0s482","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["No. LY23H030003"],"award-info":[{"award-number":["No. LY23H030003"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>\n                      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 CCl\n                      <jats:sub>4<\/jats:sub>\n                      (10% in oil) twice weekly, and nodosin (1, 5, or 10 mg\/kg\/day) was administered by gavage starting 2 weeks after CCl\n                      <jats:sub>4<\/jats:sub>\n                      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 CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced liver fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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\u2013GPX4 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Overall, nodosin alleviated CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced liver fibrosis by promoting HSC ferroptosis. These findings reveal a proteostatic mechanism linking ER stress to GPX4 stability and ferroptotic susceptibility in HSCs.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      00, 000\u2013000.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864261495029","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:33:29Z","timestamp":1791426809000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A SIRT1-PERK-HSPA5-MARCHF1 Proteostasis Axis Controls GPX4 Stability and Ferroptotic Susceptibility in Hepatic Stellate Cells"],"prefix":"10.1177","author":[{"given":"Yixiao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiya","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, 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