SMCO2 inhibits ferroptosis through the VDAC1–STAT3 axis by modulating MAM homeostasis in ovarian cancer
- 1Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
Abstract
This study identifies the previously uncharacterised transmembrane protein SMCO2 as a broadly upregulated factor in multi-organ adenocarcinomas and defines it as a novel mitochondria-associated endoplasmic reticulum membrane (MAM) structural and signalling integrator. Adenocarcinoma cells maintain metabolic adaptability and resist cell death through enhanced mitochondrial-endoplasmic reticulum communication; however, the core transmembrane regulation node that regulates this process is still unclear. Our article proves that SMCO2 interacts with VDAC1, enhances its association with STAT3, and promotes mitochondrial localisation and S727 phosphorylation of STAT3. The SMCO2-driven VDAC1–STAT3 axis modulates mitochondrial Ca²+ signalling, oxidative stress homoeostasis, and pivotal ferroptosis-associated networks, ultimately conferring ferroptosis resistance on tumour cells. Targeting SMCO2 or the VDAC1/STAT3 pathway can effectively restore ferroptosis sensitivity. Overall, our study confirms that SMCO2 is a transmembrane regulatory factor and reveals that the MAM-STAT3 axis, as a new mechanism, links metabolic adaptation to adenocarcinoma cell death resistance and has potential therapeutic significance.
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BibTeX
@article{jiang2026smco2,
title = {{SMCO2 inhibits ferroptosis through the VDAC1–STAT3 axis by modulating MAM homeostasis in ovarian cancer}},
author = {Shan Jiang and Ruqi Jiang and Yuping Du and Bingfeng Lu and Shuo Chen and Fan Shen and Jianjun Zhang and Xin Zhang and Yue Chen and Lingfeng Zhou and Yang Zhao},
journal = {Oncogene},
year = {2026},
month = oct,
doi = {10.1038/s41388-026-03983-7},
url = {https://doi.org/10.1038/s41388-026-03983-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SMCO2 inhibits ferroptosis through the VDAC1–STAT3 axis by modulating MAM homeostasis in ovarian cancer
AU - Shan Jiang
AU - Ruqi Jiang
AU - Yuping Du
AU - Bingfeng Lu
AU - Shuo Chen
AU - Fan Shen
AU - Jianjun Zhang
AU - Xin Zhang
AU - Yue Chen
AU - Lingfeng Zhou
AU - Yang Zhao
PY - 2026
DA - 2026/10/06
JO - Oncogene
DO - 10.1038/s41388-026-03983-7
UR - https://doi.org/10.1038/s41388-026-03983-7
AB - This study identifies the previously uncharacterised transmembrane protein SMCO2 as a broadly upregulated factor in multi-organ adenocarcinomas and defines it as a novel mitochondria-associated endoplasmic reticulum membrane (MAM) structural and signalling integrator. Adenocarcinoma cells maintain metabolic adaptability and resist cell death through enhanced mitochondrial-endoplasmic reticulum communication; however, the core transmembrane regulation node that regulates this process is still unclear. Our article proves that SMCO2 interacts with VDAC1, enhances its association with STAT3, and promotes mitochondrial localisation and S727 phosphorylation of STAT3. The SMCO2-driven VDAC1–STAT3 axis modulates mitochondrial Ca²+ signalling, oxidative stress homoeostasis, and pivotal ferroptosis-associated networks, ultimately conferring ferroptosis resistance on tumour cells. Targeting SMCO2 or the VDAC1/STAT3 pathway can effectively restore ferroptosis sensitivity. Overall, our study confirms that SMCO2 is a transmembrane regulatory factor and reveals that the MAM-STAT3 axis, as a new mechanism, links metabolic adaptation to adenocarcinoma cell death resistance and has potential therapeutic significance.
SN - 0950-9232
SN - 1476-5594
ER -