{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T17:27:14Z","timestamp":1786814834598,"version":"build-2736575974"},"reference-count":28,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ferroptosis contributes to aging\u2010associated functional decline, yet compounds with robust organismal efficacy and defined upstream regulatory mechanisms remain limited. Here, we established a diethyl maleate (DEM)\u2010induced glutathione depletion model in wild\u2010type (N2)\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    as a survival\u2010based screening platform and identified syringaresinol (Syr) as a leading hit from an in\u2010house small\u2010molecule library. In nematodes, Syr improved survival under DEM challenge, reduced lipid peroxidation, reactive oxygen species (ROS), and malondialdehyde levels, and alleviated age\u2010associated oxidative lipid stress and iron imbalance during natural aging, accompanied by extended lifespan and improved healthspan\u2010related phenotypes. In primary human foreskin fibroblasts, Syr conferred dose\u2010dependent protection against RSL3\u2010 or erastin\u2010induced ferroptosis, preserved cellular integrity, suppressed lipid peroxidation and ROS, and restored expression of GPX4, SLC7A11, and ferritin. In two senescence models, Syr also attenuated senescence\u2010associated phenotypes and ferroptosis\u2010related oxidative lipid stress, concomitant with recovery of GPX4 expression. Network\u2010based prediction and functional perturbation identified HIF\u20101\u03b1 as a candidate mediator of Syr\u2010associated cytoprotection. HIF\u20101\u03b1 knockdown weakened Syr\u2010mediated protection and largely prevented GPX4 restoration, whereas GPX4 knockdown did not alter HIF\u20101\u03b1 abundance. These findings support a functional HIF\u20101\u03b1\u2013GPX4 defense axis in fibroblasts, while direct transcriptional regulation remains to be clarified. Overall, Syr attenuates ferroptosis\u2010relevant oxidative lipid stress and aging\u2010associated phenotypes in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    and human fibroblast models, supporting further mechanistic and mammalian in\u00a0vivo validation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202601532r","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T16:17:54Z","timestamp":1784996274000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Syringaresinol Attenuates Aging\u2010Associated Ferroptosis\u2010Relevant Stress Through an\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1\u2013\n                    <scp>GPX4<\/scp>\n                    Defense 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Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy Southwest Medical University  Luzhou Sichuan China"},{"name":"State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China Sichuan Agricultural University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yu","sequence":"additional","affiliation":[{"name":"Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy Southwest Medical University  Luzhou Sichuan China"},{"name":"State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China Sichuan Agricultural University  Chengdu Sichuan 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