Fig. 1: Mechanism of triaptosis.
Menadione, a fat-soluble vitamin precursor, induces GSH depletion and generates ROS, leading to the oxidation of cysteine residues (Cys54 and Cys61) on PIK3C3. This oxidation results in PI(3)P depletion, causing endosomal dysfunction and triggering triaptosis. As a cellular defense mechanism, NFE2L2 activation is achieved through inhibition of KEAP1-mediated ubiquitin-proteasome degradation. This stabilization of NFE2L2 promotes its nuclear translocation, where it binds to antioxidant response elements (AREs) and drives the expression of genes involved in oxidative stress mitigation. Beyond inhibiting tumor growth, such as in prostate cancer, menadione also has therapeutic potential in treating X-linked myotubular myopathy, a fatal hereditary disease in boys caused by mutations in the MTM1 gene on the X chromosome. MTM1 is a phosphatase that antagonizes PIK3C3 kinase activity.
