CISD2 knockdown suppresses gastric cancer progression and induces ferroptosis associated with mTOR/SREBF1/SCD1 axis inhibition and GPX4 downregulation

Gastric cancer (GC) remains a major global health challenge, with diverse risk factors and etiologies, strong invasiveness, and frequent diagnosis at advanced stages. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has been extensively studied as an intrinsic tumor suppression mechanism. Notably, preliminary analyses have revealed altered expression of CDGSH iron sulfur domain 2 (CISD2) in GC tissues, yet its functional role in GC pathogenesis, particularly in the context of ferroptosis, remains completely unexplored. We found that CISD2 is significantly upregulated in GC. In vitro experiments demonstrated that knockdown of CISD2 markedly inhibited the proliferation, migration, and invasion of GC cells. Mechanistically, CISD2 knockdown induced ferroptosis, accompanied by downregulation of GPX4, and inhibition of the mTOR/SREBF1/SCD1 signaling axis. Furthermore, treatment with MHY1485, an mTOR activator, reversed the ferroptosis induced by CISD2 knockdown, further implicating mTOR signaling in this process. In vivo xenograft experiments confirmed that CISD2 knockdown significantly suppressed GC tumor growth. In summary, CISD2 plays a pro-tumorigenic role in GC. Its knockdown suppresses GC progression and induces ferroptosis, concomitant with inhibition of the mTOR/SREBF1/SCD1 axis and downregulation of GPX4. These findings suggest that CISD2 represents a potential molecular target for GC therapy.