A Mitochondria-Targeted Flavokawain A Derivative Suppresses Lymphoma by Disrupting Oxidative Phosphorylation.

Diffuse large B-cell lymphoma (DLBCL) remains clinically challenging because of drug resistance and relapse after standard therapy. In this study, we developed TPP-FLA, a mitochondria-targeted derivative of Flavokawain A (FLA) generated by conjugation with triphenylphosphonium (TPP), and evaluated its antilymphoma activity and underlying mechanism. Compared with FLA, TPP-FLA showed markedly enhanced antiproliferative activity and induced stronger lymphoma cell death and apoptosis in multiple lymphoma cell lines. Mechanistically, TPP-FLA caused pronounced mitochondrial dysfunction, as evidenced by mitochondrial membrane potential collapse detected by JC-1 staining and independently validated by Tetramethylrhodamine Methyl Ester (TMRM) staining. TPP-FLA also increased total intracellular oxidative stress, as detected by DCFH-DA, and specifically promoted mitochondria-derived superoxide accumulation, as confirmed by MitoSOX Red staining. Transcriptomic and DIA-based proteomic analyses further revealed that TPP-FLA significantly disrupted mitochondrial energy metabolism, particularly oxidative phosphorylation-related 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-FLA may therefore represent a promising mitochondria-targeted candidate for lymphoma therapy.