{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:35:08Z","timestamp":1790019308824,"version":"4.0.1"},"reference-count":135,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a global health challenge characterized by high mortality and limited therapeutic options. Recent evidence identifies ferroptosis\u2014an iron-dependent form of regulated cell death driven by the lethal accumulation of lipid peroxides\u2014as a pivotal mechanism underlying sepsis-induced organ damage. Ferroptosis Suppressor Protein 1 (FSP1) has emerged as a critical endogenous inhibitor of ferroptosis that operates independently of the canonical GPX4\/glutathione system. This review provides a comprehensive overview of recent research on FSP1 in the context of sepsis-associated organ injury. We detail the multifaceted molecular mechanisms through which FSP1 inhibits ferroptosis, including the canonical FSP1-CoQ\n                    <jats:sub>10<\/jats:sub>\n                    -NAD(P)H axis, the non-canonical vitamin K cycle, ESCRT-III-mediated membrane repair, and the newly characterized vitamin B2-dependent metabolic stability pathway. Furthermore, we highlight the newly discovered\n                    <jats:italic>STING-FSP1<\/jats:italic>\n                    signaling axis, where\n                    <jats:italic>cGAS-STING<\/jats:italic>\n                    activation transcriptionally represses FSP1, thereby driving endothelial ferroptosis and vascular leakage during sepsis. Additionally, potentially conserved pathways extrapolated from other acute injury models (e.g., ALKBH5, CD36, and SENP3) are discussed to propose novel research directions. The organ-specific roles and protective mechanisms of FSP1 in sepsis-induced injuries of the lungs, heart, liver, kidneys, and brain are systematically summarized. Finally, we evaluate the prospects and challenges of targeting FSP1-related pathways, such as Nrf2 activation and\n                    <jats:italic>STING<\/jats:italic>\n                    inhibition, as potential therapeutic strategies for sepsis. Overall, This review aims to provide new insights into the \u201cinflammation-cell death\u201d cascade in sepsis and offer a theoretical foundation for developing FSP1-targeted interventions to suppress ferroptosis.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1892904","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T10:55:09Z","timestamp":1786100109000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ferroptosis suppressor protein 1-mediated ferroptosis suppression in sepsis: non-canonical antioxidant pathways, inflammatory regulation, and therapeutic perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Yonghuan","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaiyong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ManHong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Emergency, KweiChow Moutai Hospital, Guizhou","place":["Renhuai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianping","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaf187","article-title":"Revising sepsis definitions to better target and tailor sepsis care","volume":"80","author":"Klompas","year":"2025","journal-title":"Clin Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.18-2-146","article-title":"Diagnosis and management of 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