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Triphenylphosphonium (TPP\n                    <jats:sup>+<\/jats:sup>\n                    ) is a widely used mitochondrial\u2010targeting ligand, yet its intrinsic bioactivity and mechanism remain underexplored. Here we demonstrate that alkylated TPP\n                    <jats:sup>+<\/jats:sup>\n                    derivatives exhibit chain length\u2010dependent anticancer activity, with TPP\n                    <jats:sup>+<\/jats:sup>\n                    \u2010C\n                    <jats:sub>14<\/jats:sub>\n                    showing superior efficacy both in vitro and in vivo. Mechanistically, TPP\n                    <jats:sup>+<\/jats:sup>\n                    \u2010C\n                    <jats:sub>14<\/jats:sub>\n                    selectively binds to cardiolipin, a key phospholipid in the inner mitochondrial membrane, through electrostatic and hydrophobic interactions, as validated by biolayer interferometry, competitive binding assays, and molecular dynamics simulations. This binding impairs cardiolipin function, leading to mitochondrial membrane potential collapse, adenosine triphosphate depletion, metabolic reprogramming, and ultimately mitochondrial dysfunction. Intriguingly, TPP\n                    <jats:sup>+<\/jats:sup>\n                    \u2010C\n                    <jats:sub>14<\/jats:sub>\n                    induces oncosis in cancer cells, rather than apoptosis or autophagy, by activating the endoplasmic reticulum stress pathway. These findings reveal a novel bioactive mechanism for TPP\n                    <jats:sup>+<\/jats:sup>\n                    beyond its intrinsic mitochondrial targeting property, providing a foundation for next\u2010generation mitochondrial\u2010targeted anticancer strategies that could precisely modulate mitochondrial functions.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510237","type":"journal-article","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T08:38:46Z","timestamp":1769330326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Alkyltriphenylphosphonium Binding to Cardiolipin Triggers Oncosis in Cancer Cells"],"prefix":"10.1002","volume":"13","author":[{"given":"Jin","family":"Li","sequence":"first","affiliation":[{"name":"Faculty of Medicine Dalian University of Technology  Dalian Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (MOE) Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences The Second Hospital Cheeloo College of Medicine Shandong University Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (MOE) Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijia","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (MOE) Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangrong","family":"Lou","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Dalian University of Technology  Dalian Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Dalian University of Technology  Dalian Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-5324","authenticated-orcid":false,"given":"Zhao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology (MOE) Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjun","family":"Wu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Dalian University of Technology  Dalian Liaoning China"},{"name":"School of Life and Health Sciences Qingdao Central Hospital University of Health and Rehabilitation Sciences  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-28637-2"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001839\u20108"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010023\u201000783\u20101"},{"key":"e_1_2_8_5_1","volume-title":"Reviews of Physiology, Biochemistry and Pharmacology 176","author":"Loh K. 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