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In this study, we developed TPP\u2010FLA, a mitochondria\u2010targeted derivative of Flavokawain A (FLA) generated by conjugation with triphenylphosphonium (TPP), and evaluated its antilymphoma activity and underlying mechanism. Compared with FLA, TPP\u2010FLA showed markedly enhanced antiproliferative activity and induced stronger lymphoma cell death and apoptosis in multiple lymphoma cell lines. Mechanistically, TPP\u2010FLA caused pronounced mitochondrial dysfunction, as evidenced by mitochondrial membrane potential collapse detected by JC\u20101 staining and independently validated by Tetramethylrhodamine Methyl Ester (TMRM) staining. TPP\u2010FLA also increased total intracellular oxidative stress, as detected by DCFH\u2010DA, and specifically promoted mitochondria\u2010derived superoxide accumulation, as confirmed by MitoSOX Red staining. Transcriptomic and DIA\u2010based proteomic analyses further revealed that TPP\u2010FLA significantly disrupted mitochondrial energy metabolism, particularly oxidative phosphorylation\u2010related pathways. Collectively, these findings demonstrate that TPP conjugation substantially enhances the antilymphoma activity of FLA by inducing mitochondrial depolarization, oxidative stress, and oxidative phosphorylation disruption. TPP\u2010FLA may therefore represent a promising mitochondria\u2010targeted candidate for lymphoma therapy.<\/jats:p>","DOI":"10.1002\/cplu.202500691","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:04:57Z","timestamp":1781499897000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mitochondria\u2010Targeted Flavokawain A Derivative Suppresses Lymphoma by Disrupting Oxidative Phosphorylation"],"prefix":"10.1002","volume":"91","author":[{"given":"Shufang","family":"Fan","sequence":"first","affiliation":[{"name":"Health science center Ningbo University  Ningbo China"},{"name":"Department of Hematology The First Affiliated Hospital of Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanchuan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Hematology Lianyungang Second People\u2019s Hospital  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