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

Juan Yang, Xiao Lu, Jing-Lan Hao, Lan Li, Yong-Tong Ruan, Xue-Ni An, Qi-Lai Huang, Xiao-Ming Dong () and Ping Gao ()
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Juan Yang: Shaanxi Normal University
Xiao Lu: Shaanxi Normal University
Jing-Lan Hao: Shaanxi Normal University
Lan Li: Shaanxi Normal University
Yong-Tong Ruan: Shaanxi Normal University
Xue-Ni An: Shaanxi Normal University
Qi-Lai Huang: Shandong University
Xiao-Ming Dong: Shaanxi Normal University
Ping Gao: Shaanxi Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56494-6

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