{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:41:25Z","timestamp":1792690885565,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Indroduction<\/jats:title><jats:p>Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, represents a novel therapeutic target for myocardial injury. Salidroside (SAL), a natural bioactive compound derived from Rhodiola rosea, exhibits cardioprotective effects through multi-target mechanisms with minimal adverse effects, yet its precise role in ferroptosis regulation remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study systematically investigated SAL\u2019s anti-ferroptotic effects using <jats:italic>in vitro<\/jats:italic> (RSL3-induced H9C2 cardiomyocytes) and <jats:italic>in vivo<\/jats:italic> (DOX-induced myocardial injury mouse model) approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SAL treatment significantly enhanced cardiomyocyte viability by attenuating ferroptotic hallmarks, including lipid ROS accumulation, iron overload, lipid peroxidation, and mitochondrial dysfunction. Transcriptomic analysis revealed SAL-mediated modulation of DNA replication\/repair, cell cycle regulation, protein autophosphorylation, drug ADME processes, and glutathione metabolism\u2014a critical pathway in ferroptosis. Molecular docking identified \u03b3-glutamyltransferase 1 (GGT1) as a high-affinity SAL target, linking drug metabolism and glutathione homeostasis. In MI mice, SAL downregulated GGT1 expression while restoring ferroptosis-related biomarkers: upregulating GPX4 and reducing SLC7A11\/LC3II levels. Mechanistically, SAL suppresses ferroptosis through dual regulation of GGT1: (1) enhancing glutathione synthesis via GGT1 inhibition and (2) potentiating GPX4-mediated antioxidant defense.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings establish GGT1 as a pivotal therapeutic target for SAL\u2019s cardioprotection, providing a mechanistic basis for its clinical application in ferroptosis-associated cardiovascular diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1580506","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T09:02:07Z","timestamp":1747213327000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Salidroside can protect against ferroptosis in cardiomyocytes and may be related to the regulation of GGT1"],"prefix":"10.3389","volume":"16","author":[{"given":"Tianhang","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghua","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyou","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.2174\/1389557519666190903115424","article-title":"Rhodiola and salidroside in the treatment of metabolic disorders","volume":"19","author":"Bai","year":"2019","journal-title":"Mini Rev. 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