Cepharanthine-Mediated Sonodynamic Action Induces Robust Mitochondrial Damage Through Regulation of Drp-1 Phosphorylation Against Lung Cancer.

Sonodynamic therapy (SDT), an emerging anti-cancer strategy, utilizes ultrasound (US) to activate sonosensitizers derived from natural products, thereby generating singlet oxygen to destroy tumor cells. Cepharanthine (Cep) is a natural phytomedicine with inherent anti-tumor activity, whose efficacy was significantly enhanced by US discovered in the present work. This study aims to further investigate the specific drug target of Cep relevant to SDT/mitochondria and to evaluate the therapeutic effects of Cep-mediated SDT on lung cancer cells and mice. Our findings revealed that Cep binds to dynamin-related protein 1 (Drp1) and inhibits its phosphorylation through SDT, leading to excessive mitochondrial fission. This disruption resulted in severe mitochondrial oxidative stress and subsequent damage. The critical role of Drp1 in this process was confirmed by rescue experiments, wherein overexpression of Drp1 further amplified Cep SDT-induced mitochondrial damage and mitigated its anti-cancer effects in vitro. Ultimately, this mechanism translated into profound therapeutic outcomes: Cep SDT effectively abolished the proliferation and boosted the apoptosis of lung cancer cells. Furthermore, it exhibited a favorable inhibitory effect on tumor growth in mouse models, underscoring its translational potential. To conclude, Cep binds to Drp1 (functional mediator) within lung cancer cells, upon US application, shifts its phosphorylation balance by decreasing inhibitory and increasing activating modifications. This Drp1 hyperactivation triggers excessive mitochondrial fission, which selectively compromises mitochondrial integrity and results in potent SDT destroying of the cancer cells. Our work provides important insights into phytomedicine-based SDT and represents a pioneering exploratory application.