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The renin\u2013angiotensin system (RAS), particularly its non\u2010canonical arm, has been implicated in tissue protection, yet its crosstalk with ferroptosis remains underexplored. This study investigated the hepato\u2010therapeutic potential of xanthenone (XNT), an ACE2 activator, in a LLTI\u2010induced liver injury model, with a focus on the Ang\u2010(1\u20139)\/AT2R axis and ferroptosis regulation. Accordingly, male Wistar rats were subjected to LLTI and treated with XNT, with or without the AT2R antagonist PD123319. Hepatic function, oxidative stress markers, ferroptotic signals, and RAS components were assessed using molecular modeling, biochemical, and histopathological techniques. XNT improved liver architecture and reduced ALT\/AST levels to confer hepatoprotection. Mechanistically, XNT shifted RAS signaling to the protective ACE2\/Ang\u2010(1\u20139)\/AT2R pathway, leading to suppression of Ang\u2010II and enhancement of Ang\u2010I\/Ang\u2010(1\u20139) contents. This shift activated the AKT\/Nrf2\/HO\u20101 antioxidant cascade and restored homeostasis of the central anti\u2010ferroptotic system SLC7A11\/GSH\/GPX4, inhibited ACSL4 expression, thereby reducing ROS, and lipid peroxidation. Importantly, XNT also mitigated ferroptosis by downregulating Fe\n                    <jats:sup>3+<\/jats:sup>\n                    \/TfR1, Fe\n                    <jats:sup>2+<\/jats:sup>\n                    , and ferritin accumulation, while modulating the ferritinophagy axis through upregulation of HERC2 and suppression of NCOA4. These effects were largely abolished by PD123319, indicating AT2R dependency. In conclusion, XNT protects against LLTI\u2010induced hepatic injury by orchestrating a dual antioxidant and anti\u2010ferroptotic response via the Ang\u2010(1\u20139)\/AT2R axis. These findings unveil a novel crosstalk between RAS modulation and ferroptosis regulation, positioning AT2R activation as a promising therapeutic strategy for ischemia\/reperfusion\u2010related liver damage.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70236","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:40:31Z","timestamp":1775842831000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Xanthenone Orchestrates the Renin\u2013Angiotensin System\/Ferroptosis Crosstalk: A Novel AT2R\u2010Dependent Strategy Against Lower Limb Transient Ischemia\u2010Induced Liver Injury"],"prefix":"10.1002","volume":"359","author":[{"given":"Miar M.","family":"Sherif","sequence":"first","affiliation":[{"name":"Postgraduate Program in Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt"},{"name":"Egyptian Drug Authority (EDA) Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5876-5530","authenticated-orcid":false,"given":"Dalaal M.","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iten M.","family":"Fawzy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Future University in Egypt Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanan S.","family":"El\u2010Abhar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy Future University in Egypt Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2012.04.024"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yasu.2022.03.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-48858-z"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5606\/tgkdc.dergisi.2020.18631"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43094-025-00781-y"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12517"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-024-1080-8"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2025.167912"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2298-2"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-021-07220-z"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-024-04161-5"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade9585"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2023.0005"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.7860\/JCDR\/2012\/4410.2533"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","unstructured":"J.Pei X.Pan G.Wei andY.Hua Frontiers in Pharmacology14 (2023): 1147414 https:\/\/doi.org\/10.3389\/fphar.2023.1147414.","DOI":"10.3389\/fphar.2023.1147414"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115021"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200220666190227224748"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","unstructured":"H.KuwataandS.Hara Prostaglandins & Other Lipid Mediators144 (2019): 106363 https:\/\/doi.org\/10.1016\/j.prostaglandins.2019.106363.","DOI":"10.1016\/j.prostaglandins.2019.106363"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.85674"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05716-0"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00618.2005"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00038.2017"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20245138"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"F. 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