SAT1-Mediated Spermidine Metabolism Drives Ferroptosis in Cervical Cancer

Background Spermidine (SPD) dysregulation is common in multiple cancers and is associated with reduced survival of cervical cancer (CC) cells. However, the mechanisms underlying SPD's role in CC progression remain poorly understood. This study aimed to investigate how SPD metabolism influences ferroptosis in cervical cancer. Methods Using bioinformatics analysis of public databases and immunohistochemistry on clinical specimens, we assessed the expression of SPD metabolic enzymes. In vitro experiments were conducted using HeLa and SiHa cervical cancer cell lines. Cell viability was measured by CCK-8 assay, mitochondrial morphology was observed via transmission electron microscopy, and protein expression was analyzed by Western blot. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were quantified using fluorescent probes and biochemical assays. Statistical significance was determined using Student’s t-test or one-way ANOVA. Results We identified elevated expression of the rate-limiting SPD metabolic enzyme SAT1 in cervical cancer tissues. SPD treatment induced ferroptosis in CC cells, as demonstrated by decreased Glutathione Peroxidase 4 (GPX4) expression, increased ROS and MDA levels, and characteristic mitochondrial alterations. Overexpression of SAT1 or supplementation with its downstream metabolite N ¹ -acetylspermidine enhanced ferroptosis. Importantly, both SPD and N ¹ -acetylspermidine attenuated the ferroptosis resistance caused by SAT1 inhibition. Conclusion Our findings reveal that enhanced SAT1-mediated SPD metabolism promotes ferroptosis in cervical cancer, suggesting that targeting this metabolic pathway could represent a novel therapeutic strategy for CC treatment.