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Herein, we report a mitochondria-directed Pt(IV) prodrug, LA-Pt(IV), in which lipoic acid (LA) serves as a metabolite-reactive axial ligand enabling selective tumor suppression. Upon cellular internalization, LA-Pt(IV) preferentially accumulates in the mitochondria and undergoes intracellular reduction to release cytotoxic Pt(II) species together with lipoic acid-derived dihydrolipoic acid (DHLA). While the Pt(II) species induce DNA damage, DHLA undergoes the Michael addition reaction with endogenous ubiquinone (UQ), thereby depleting this key electron carrier and disrupting mitochondrial electron transport. This process triggers profound mitochondrial dysfunction, bioenergetic collapse, and a lethal burst of reactive oxygen species (ROS). Notably, LA-Pt(IV) exhibits markedly enhanced potency and selectivity toward multiple cancer cell lines relative to cisplatin. In vivo studies confirmed that LA-Pt(IV) achieves potent tumor inhibition with substantially reduced systemic toxicity. This work establishes a dual-targeting strategy for platinum drug design by incorporating the reactive ligand to perturb endogenous metabolism associated with mitochondrial electron transport.<\/jats:p>","DOI":"10.1021\/acsabm.6c01398","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:02:20Z","timestamp":1788890540000},"page":"8878-8888","source":"Crossref","is-referenced-by-count":0,"title":["A Ubiquinone-Reactive Pt(IV) Prodrug Perturbs Mitochondrial Metabolism for Selective Tumor Suppression"],"prefix":"10.1021","volume":"9","author":[{"given":"Yi","family":"Dai","sequence":"first","affiliation":[{"name":"Anhui Xinhua University , , ,","place":["Hefei, China, 230088"]},{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Yu","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5434-1869","authenticated-orcid":true,"given":"Yichen","family":"Yin","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyun","family":"Zheng","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2414-5346","authenticated-orcid":true,"given":"Zhaolin","family":"Chen","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-7964","authenticated-orcid":true,"given":"Yangzhong","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026092100084602000_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115323","article-title":"Cisplatin in cancer treatment","volume":"206","author":"Romani","year":"2022","journal-title":"Biochem. 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