VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis
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...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56494-6 |
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| author | Juan Yang Xiao Lu Jing-Lan Hao Lan Li Yong-Tong Ruan Xue-Ni An Qi-Lai Huang Xiao-Ming Dong Ping Gao |
| author_facet | Juan Yang Xiao Lu Jing-Lan Hao Lan Li Yong-Tong Ruan Xue-Ni An Qi-Lai Huang Xiao-Ming Dong Ping Gao |
| author_sort | Juan Yang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-06d61b4a20984828b58d89b221ac4439 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-06d61b4a20984828b58d89b221ac44392025-02-02T12:32:32ZengNature PortfolioNature Communications2041-17232025-01-0116112110.1038/s41467-025-56494-6VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasisJuan Yang0Xiao Lu1Jing-Lan Hao2Lan Li3Yong-Tong Ruan4Xue-Ni An5Qi-Lai Huang6Xiao-Ming Dong7Ping Gao8College of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityShandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong UniversityCollege of Life Sciences, Shaanxi Normal UniversityCollege of Life Sciences, Shaanxi Normal UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56494-6 |
| spellingShingle | Juan Yang Xiao Lu Jing-Lan Hao Lan Li Yong-Tong Ruan Xue-Ni An Qi-Lai Huang Xiao-Ming Dong Ping Gao VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis Nature Communications |
| title | VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis |
| title_full | VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis |
| title_fullStr | VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis |
| title_full_unstemmed | VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis |
| title_short | VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis |
| title_sort | vstm2l protects prostate cancer cells against ferroptosis via inhibiting vdac1 oligomerization and maintaining mitochondria homeostasis |
| url | https://doi.org/10.1038/s41467-025-56494-6 |
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