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While mitophagy activation has been shown to attenuate apoptosis and pyroptosis, thereby ameliorating CI\/RI, the therapeutic potential of natural compounds targeting this pathway remains underexplored.\n                      <jats:italic>Penthorum chinense<\/jats:italic>\n                      Pursh (PCP), a traditional hepatoprotective herb, contains Thonningianin A (TA), a bioactive compound with reported autophagic properties. However, the role and mechanisms of TA in CI\/RI mitigation remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vivo, a middle cerebral artery occlusion\/reperfusion (MCAO\/R) rat model was established to evaluate TA\u2019s neuroprotective effects via TTC staining, Longa neurological scoring, and immunofluorescence staining. In vitro, oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R)-treated HT22 and BV2 cells were used to assess TA\u2019s impact on cell viability (MTT, Hoechst\/PI staining), mitochondrial oxidative stress (DHE, TMRM, JC-1, Mito-Tracker staining and Western blot), apoptosis (flow cytometry, immunofluorescence staining, Hochest and PI staining and Western blot), and pyroptosis (EthD-2\/YO-PRO-1 staining and Western blot). Autophagy and mitophagy modulation was investigated using rapamycin (Rap), 3-MA (autophagy inhibitor), CCCP (mitophagy inducer), and AC220 (mitophagy inhibitor) in EGFP-LC3-U87 and mCherry-GFP-FIS1-293T cells. Co-localization immunofluorescence and Western blotting were employed to validate PINK1\/Parkin pathway involvement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TA administration significantly improved neurological function, reduced cerebral infarct volume, and attenuated neuronal damage in MCAO\/R rats. In vitro, TA suppressed OGD\/R-induced mitochondrial oxidative stress and apoptosis in HT22 cells while mitigating pyroptosis in BV2 microglia. Mechanistically, TA activated PINK1\/Parkin-dependent mitophagy, as evidenced by enhanced LC3-II\/I ratio, and increased mitochondrial-autophagosome co-localization. Crucially, TA\u2019s anti-apoptotic and anti-pyroptotic effects were abolished upon mitophagy inhibition. These findings were corroborated in the MCAO\/R model, where TA upregulated PINK1\/Parkin signaling and mitigated cell damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies TA as a novel natural agent alleviating CI\/RI by activating PINK1\/Parkin-mediated mitophagy, thereby concurrently suppressing apoptosis and pyroptosis. These findings provide the first elucidating the molecular mechanis underlying TA's potential as a therapeutic candidate for IS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13020-025-01247-2","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:34:15Z","timestamp":1768530855000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Thonningianin A derived from Penthorum chinense Pursh alleviates cerebral ischemia\/reperfusion-mediated apoptosis and pyroptosis through the activation of PINK1\/Parkin-dependent mitophagy"],"prefix":"10.1186","volume":"21","author":[{"given":"Qianfang","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guishan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anguo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqiang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalian","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty Yuen-Kwan","family":"Law","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-9138","authenticated-orcid":false,"given":"Lu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"issue":"5","key":"1247_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S1474-4422(19)30030-4","volume":"18","author":"PB Gorelick","year":"2019","unstructured":"Gorelick PB. 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