miR-29a-3p regulates SPARC to inhibit ferroptosis and promote cell proliferation in gastric cancer.

Ferroptosis, an iron-dependent, non-apoptotic form of cell death, is a promising therapeutic target in cancer. Secreted protein acidic and rich in cysteine (SPARC) contributes to the pathogenesis of gastric cancer (GC); however, whether SPARC modulates ferroptosis in GC cells remains unclear. Ferroptosis-related genes in GC were identified through bioinformatics screening. Ferroptosis was induced (Erastin) or inhibited (Ferrostatin-1), followed by analyses of GSH, MDA, and SOD activity. mRNA and protein expression was quantified via qRT-PCR, immunohistochemistry, and western blotting. The miR-29a-3p/SPARC interaction was confirmed by a dual-luciferase reporter assay. Cell proliferation was assessed using MTT and EdU assays. In vivo effects of SPARC on tumor growth and ferroptosis were evaluated in a xenograft mouse model. SPARC was identified as a ferroptosis-related gene in GC. Its expression was significantly lower in GC tissues than in adjacent normal gastric tissues and was negatively correlated with tumor size and differentiation. Low expression was an independent predictor of shorter overall survival in GC patients. Functionally, SPARC attenuated GC cell proliferation by promoting ferroptosis. SPARC was identified as a direct downstream target of miR-29a-3p, which inhibited ferroptosis in GC cells by suppressing SPARC expression. Furthermore, we demonstrated that SPARC overexpression significantly suppressed GC tumor growth and induced ferroptosis in vivo. This study suggests that miR-29a-3p directly targets and represses SPARC expression, which may promote GC tumor proliferation by inhibiting ferroptosis in cellular models. The miR-29a-3p/SPARC axis may represent a potential therapeutic target for GC, but its clinical translational relevance requires further validation in larger cohorts.