{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:10:29Z","timestamp":1780319429537,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T00:00:00Z","timestamp":1780185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010814","name":"foundation of Anhui Provincial Key Laboratory of Chinese Medicinal Formula","doi-asserted-by":"publisher","award":["2025AKLCMF05"],"award-info":[{"award-number":["2025AKLCMF05"]}],"id":[{"id":"10.13039\/501100010814","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Excellent Research and Innovation Team of Universities in Anhui Province","award":["2022AH010034"],"award-info":[{"award-number":["2022AH010034"]}]},{"name":"Key Natural Science Research Projects of Universities in Anhui Province","award":["KJ2020A0410"],"award-info":[{"award-number":["KJ2020A0410"]}]},{"name":"International Scientific and Technological Cooperation Projects of Key Research and Development Plan of Anhui Province","award":["2022h11020019"],"award-info":[{"award-number":["2022h11020019"]}]},{"name":"Anhui Province 13th batch 115 industrial innovation team \u201cInnovative team for the prevention and treatment of encephalopathy with a combination of acupuncture and medicine\u201d project","award":["4"],"award-info":[{"award-number":["4"]}]},{"name":"Foundation of Anhui Province Key Laboratory of Bioactive Natural Products","award":["AKLPDCM202307"],"award-info":[{"award-number":["AKLPDCM202307"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Hydroxysafflor Yellow A (HSYA), the major bioactive component from Carthamus tinctorius L., exerts significant protective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy is pivotal in the pathological process of MIRI, yet the specific molecular mechanism underlying HSYA-mediated mitophagy regulation remains unclear. Objective: This study aimed to investigate the association between HSYA treatment and mitochondrial autophagy in murine MIRI and to explore the potential mechanistic role of the SIRT1-FOXO3-BNIP3 signaling pathway using functional loss-of-function and rescue experiments. These findings may provide preliminary evidence supporting the clinical translational potential in MIRI therapy. Methods: Mouse myocardial ischemia-reperfusion injury (MIRI) model and oxygen-glucose deprivation\/reoxygenation (OGD\/R)-induced AC16 cardiomyocyte injury models were established. Metabolomics, molecular docking, and surface plasmon resonance (SPR) techniques were combined to screen the potential targets of HSYA. The SIRT1 inhibitor EX527 and SIRT1 siRNA were used to verify the underlying mechanism. Cardiac function, myocardial infarct size, mitochondrial function, the expression of autophagy-related proteins, and protein\u2013protein interaction were detected and analyzed. Results: Compared with the MIRI group, HSYA significantly improved cardiac function in mice, as evidenced by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (p &lt; 0.01), attenuated ST-segment elevation, and improved myocardial perfusion. HSYA also markedly reduced myocardial infarct size (p &lt; 0.01) and serum levels of CK-MB, LDH, and cTnI (all p &lt; 0.01) and ameliorated myocardial histopathological damage and mitochondrial ultrastructural integrity. Mechanistic studies revealed that HSYA significantly upregulated the expression of SIRT1, FOXO3, BNIP3, Beclin-1, and the LC3II\/I ratio while downregulating p62 expression (p &lt; 0.01), consistent with enhanced mitophagy-related activity. Furthermore, these protective effects were markedly attenuated upon SIRT1 inhibition or siRNA-mediated silencing, whereas HSYA intervention partially reversed these alterations. Additionally, co-immunoprecipitation (Co-IP) and pull-down assays demonstrated that HSYA promoted protein\u2013protein interactions between SIRT1-FOXO3, FOXO3-BNIP3, and BNIP3-LC3B. Conclusions: These findings highlight that HSYA is associated with improved cardiac function, enhanced mitophagy-related activity, and upregulated SIRT1-FOXO3-BNIP3 signaling, providing robust experimental evidence for its clinical translational application in MIRI treatment.<\/jats:p>","DOI":"10.3390\/nu18111780","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"1780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydroxysafflor Yellow A Regulates SIRT1-FOXO3-BNIP3 Signaling Pathway to Promote Mitophagy: A Novel Therapeutic Strategy for Myocardial Ischemia-Reperfusion Injury"],"prefix":"10.3390","volume":"18","author":[{"given":"Dongdong","family":"Meng","sequence":"first","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Traditional Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencong","family":"Xia","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Traditional Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Tian","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Traditional Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Huang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Anhui Province Key Laboratory of Bioactive Natural Products, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2528-6523","authenticated-orcid":false,"given":"Chaowen","family":"Ge","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Traditional Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China"},{"name":"Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Traditional Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1093\/cvr\/cvaf203","article-title":"Recent progress regarding the role of autophagy in cardiac disease","volume":"121","author":"Maejima","year":"2025","journal-title":"Cardiovasc. 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