ABSTRACT Mitochondria, pivotal for cellular bioenergetics and signaling, are attractive targets for cancer therapy. Triphenylphosphonium (TPP + ) is a widely used mitochondrial‐targeting ligand, yet its intrinsic bioactivity and mechanism remain underexplored. Here we demonstrate that alkylated TPP + derivatives exhibit chain length‐dependent anticancer activity, with TPP + ‐C 14 showing superior efficacy both in vitro and in vivo. Mechanistically, TPP + ‐C 14 selectively binds to cardiolipin, a key phospholipid in the inner mitochondrial membrane, through electrostatic and hydrophobic interactions, as validated by biolayer interferometry, competitive binding assays, and molecular dynamics simulations. This binding impairs cardiolipin function, leading to mitochondrial membrane potential collapse, adenosine triphosphate depletion, metabolic reprogramming, and ultimately mitochondrial dysfunction. Intriguingly, TPP + ‐C 14 induces oncosis in cancer cells, rather than apoptosis or autophagy, by activating the endoplasmic reticulum stress pathway. These findings reveal a novel bioactive mechanism for TPP + beyond its intrinsic mitochondrial targeting property, providing a foundation for next‐generation mitochondrial‐targeted anticancer strategies that could precisely modulate mitochondrial functions.
Li et al. (Sun,) studied this question.