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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Arsenic trioxide (ATO) is a first-line therapeutic agent for acute promyelocytic leukemia (APL), but its clinical utility is constrained by dose-dependent cardiotoxicity. This study aimed to systematically evaluate the cytoprotective potential of dihydroquercetin (DHQ), a natural flavonoid derived from coniferous species with multimodal antioxidant properties, against ATO-induced cellular injury. An integrated combining network pharmacology with experimental validation was employed to elucidate the underlying molecular mechanisms. Cardiotoxicity models were established using AC16 human cardiomyocytes and human umbilical vein endothelial cells (HUVECs). Cytotoxicity, reactive oxygen species (ROS), mitochondrial membrane potential, DNA damage (\u03b3-H2AX), apoptosis (TUNEL, Bcl-2, Bax, Caspase-3), and ferroptosis markers (GPX4, xCT, intracellular iron) were assessed. The AMPK\/SIRT1\/PGC-1\u03b1 axis was validated using Compound C. ATO exposure induced significant cytotoxicity, oxidative stress, mitochondrial dysfunction, and activated both apoptosis and ferroptosis pathways. Co-treatment with DHQ dose-dependently attenuated these injuries. Mechanistically, DHQ activated AMPK\/SIRT1\/PGC-1\u03b1, increasing phosphorylated AMPK, SIRT1, and PGC-1\u03b1. Compound C abrogated DHQ-mediated pathway activation and its protection against oxidative stress, apoptosis, and ferroptosis. DHQ protects against ATO cardiotoxicity by activating the AMPK\/SIRT1\/PGC-1\u03b1 pathway, thereby reducing oxidative stress and concurrently inhibiting apoptosis and ferroptosis. These findings position DHQ as a promising candidate for protecting cardiomyocytes and endothelial cells from ATO-induced injury.<\/jats:p>","DOI":"10.3390\/ijms27198753","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:59:25Z","timestamp":1790765965000},"page":"8753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dihydroquercetin Activates AMPK\/SIRT1\/PGC-1\u03b1 Signaling to Attenuate Arsenic Trioxide-Induced Apoptosis and Ferroptosis in AC16 Cells and HUVECs"],"prefix":"10.3390","volume":"27","author":[{"given":"Wenlei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Rui","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Xinsheng","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Sijing","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Haoxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Jinyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xinru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Lijuan","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Kai","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Tianyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Meihua","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Xiaoxiang","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of 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