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Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099555), we have identified isoginkgetin (ISO), a bioflavonoid from\n                    <jats:italic>Ginkgo biloba<\/jats:italic>\n                    , as a robust and specific mitophagy inducer. ISO enhances PINK1\u2013Parkin-dependent mitophagy via stabilization of the PINK1\/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1\u2013Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.\n                  <\/jats:p>","DOI":"10.1038\/s44321-025-00323-2","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T15:35:57Z","timestamp":1760542557000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy"],"prefix":"10.1038","volume":"17","author":[{"given":"Ang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-qin","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3912-0056","authenticated-orcid":false,"given":"Linping","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6600-8804","authenticated-orcid":false,"given":"Miaodan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoyuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong U","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajiang","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1147-125X","authenticated-orcid":false,"given":"Jiahong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2268-1033","authenticated-orcid":false,"given":"Guang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7369-5227","authenticated-orcid":false,"given":"Hanming","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-7956","authenticated-orcid":false,"given":"Xiaoli","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-7202","authenticated-orcid":false,"given":"Evandro F","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3254-825X","authenticated-orcid":false,"given":"Huanxing","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"323_CR1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.brainres.2011.02.060","volume":"1394","author":"CJ Alves","year":"2011","unstructured":"Alves CJ, de Santana LP, dos Santos AJ, de Oliveira GP, Duobles T, Scorisa JM, Martins RS, Maximino JR, Chadi G (2011) Early motor and electrophysiological changes in transgenic mouse model of amyotrophic lateral sclerosis and gender differences on clinical outcome. 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