Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis

Mitochondria-targeted delivery is a promising strategy in anticancer drug development. Triphenylphosphine cation (TPP⁺) is the most widely used mitochondrial-targeting carrier due to the elevated mitochondrial membrane potential (MMP) in cancer cells. Here, we report the serendipitous discovery of a mitochondrial-targeting carrier, compound 23, which exhibited potent anticancer activity (IC₅₀ = 70 nM, HCC827) with minimal toxicity to normal cells. Compound 23 selectively accumulates in cancer cell mitochondria, induces MMP depolarization, and activates mitophagy via PINK1-Parkin pathway. It also disruptes mitochondrial functions, elevates ROS levels, and inhibits the xCT-GSH-GPX4 axis, leading to lipid peroxidation and ferroptotic cell death. In vivo, 23 significantly suppressed the growth of HCC827 xenograft tumors at 10 mg/kg. These findings support compound 23 as a highly selective and effective mitochondrial-targeting anticancer agent for further investigation.