Triaptosis: an emerging endosome-centered mechanism of ROS-regulated cell death

Abstract Reactive oxygen species (ROS) are central regulators of cell fate that shape regulated cell death (RCD) through spatially organized and context-dependent redox signaling. Established ROS‑driven RCD pathways, including apoptosis, ferroptosis, necroptosis, and pyroptosis, have largely been interpreted through mitochondrial dysfunction, lipid peroxidation, inflammatory signaling, and DNA damage. Triaptosis expands this framework by defining an endosome-centered, redox-dependent cell death pathway. In triaptosis, oxidative stress inactivates the class III phosphatidylinositol 3-kinase (PIK3C3, also known as VPS34), leading to depletion of phosphatidylinositol 3-phosphate (PI3P). This loss of PI3P disrupts PI3P-dependent endosomal identity, which in turn impairs vesicular trafficking. This culminates in the accumulation of enlarged dysfunctional vacuoles and progressive cellular collapse. Triaptosis is mechanistically distinct from canonical RCD programs because it proceeds despite the inhibition of caspases, necroptotic signaling, and lipid peroxidation, and is instead defined by ROS‑driven failure of endosomal homeostasis. Cellular susceptibility to triaptosis is governed by redox buffering capacity, particularly glutathione (GSH) levels and activity of the Kelch‑like ECH‑associated protein 1 (KEAP1)-nuclear factor erythroid 2‑related factor 2 (NRF2) pathway, which together set the threshold for VPS34 oxidation and PI3P loss. Here, we integrate triaptosis into the broader ROS-RCD network, distinguish it from other ROS-associated death pathways, and discuss its emerging therapeutic potential, particularly in cancer where near‑threshold redox states may render tumors selectively vulnerable to endosomal collapse. Triaptosis therefore provides a potential framework for organelle-specific redox-regulated cell death, suggesting that ROS-mediated cytotoxicity may, in some contexts, arise through targeted organelle failure alongside mitochondrial dysfunction, lipid peroxidation, and nuclear damage.