SMCO2 inhibits ferroptosis through the VDAC1–STAT3 axis by modulating MAM homeostasis in ovarian cancer

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.