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Alkyltriphenylphosphonium Binding to Cardiolipin Triggers Oncosis in Cancer Cells

Jin Li1, Hang Zheng2, Yuxing Lin3

  • 1Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 25, 2026
PubMed

Insights

Triphenylphosphonium-C14 (TPP+-C14) selectively targets cardiolipin in mitochondria, disrupting cellular energy and inducing cancer cell oncosis. This reveals a new mechanism for TPP+-based anticancer drug development.

Area of Science:

  • Mitochondrial biology
  • Cancer therapeutics
  • Molecular pharmacology

Background:

  • Mitochondria are crucial for cellular energy and signaling, making them key targets for cancer therapy.
  • Triphenylphosphonium (TPP+) is a common mitochondrial-targeting ligand, but its inherent biological activity and precise mechanism are not fully understood.

Purpose of the Study:

  • To investigate the anticancer activity and underlying mechanisms of alkylated Triphenylphosphonium (TPP+) derivatives.
  • To explore the selective targeting of cardiolipin by TPP+-C14 and its impact on mitochondrial function and cancer cell death.

Main Methods:

  • Synthesis and evaluation of alkylated TPP+ derivatives for anticancer efficacy in vitro and in vivo.
  • Biolayer interferometry, competitive binding assays, and molecular dynamics simulations to determine TPP+-C14 binding to cardiolipin.
  • Assessment of mitochondrial function, including membrane potential and ATP levels, and analysis of cancer cell death pathways (oncosis, apoptosis, autophagy).

Main Results:

  • Alkylated TPP+ derivatives demonstrated chain length-dependent anticancer activity, with TPP+-C14 being the most effective.
  • TPP+-C14 selectively binds to cardiolipin in the inner mitochondrial membrane via electrostatic and hydrophobic interactions.
  • TPP+-C14 binding induced mitochondrial membrane potential collapse, ATP depletion, metabolic reprogramming, and ultimately mitochondrial dysfunction.
  • TPP+-C14 triggered oncosis in cancer cells by activating the endoplasmic reticulum stress pathway, distinct from apoptosis or autophagy.

Conclusions:

  • TPP+-C14 exhibits potent anticancer activity through a novel mechanism involving selective cardiolipin binding and induction of oncosis.
  • These findings expand the understanding of TPP+ bioactivity beyond mere mitochondrial targeting.
  • The study provides a basis for developing next-generation mitochondrial-targeted cancer therapies that precisely modulate mitochondrial functions.
Keywords:
cancer cellscardiolipinmitochondriaoncosistriphenylphosphonium

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