13-Decyl Berberine Derivative Is a Novel Mitochondria-Targeted Antioxidant and a Potent Inhibitor of Ferroptosis.

Berberine is a plant isoquinoline alkaloid widely used in traditional medicine for the therapy of diabetes, cardiovascular and other diseases. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, is thought to contribute to the pathogenesis of various diseases associated with excessive oxidative stress. The therapeutic actions of berberine are mediated, at least in part, by its antioxidant effects. Here, we report that the lipophilic berberine derivative 13-decyl berberine (C10Berb) is a mitochondria-targeted antioxidant that exhibits superior ferroptosis inhibition compared to native berberine in H9c2 cardiomyocytes and human fibroblasts. C10Berb efficiently accumulates in mitochondria, suppressing both mitochondrial lipid peroxidation, reactive oxygen species formation, and lipofuscin accumulation at concentrations markedly lower than berberine. Mechanistic studies indicate that the anti-ferroptotic effect of C10Berb is independent of AMPK or Nrf2 activation and is primarily due to its direct antioxidant activity in mitochondria. In isolated cardiac mitochondria, C10Berb potently inhibited lipid peroxidation induced by either reactive oxygen species produced in the electron transport chain or artificial free radical initiators. These results support the hypothesis that mitochondrial lipid peroxidation is critical for ferroptosis and highlight the potential of mitochondria-targeted berberine derivatives as promising therapeutic agents for conditions associated with ferroptotic cell death.