VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from Apoptosis, necrosis, and Autophagy. Mitochondria play a critical role in initiating and amplifying Ferroptosis in Cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of Ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating Ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set and Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, is positively associated with prostate Cancer (PCa) progression, and a key regulator of Ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced Ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and Hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting Ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving Ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.