<i>NSUN2</i> mediates <i>SALL2</i> m5C methylation to inhibit ferroptosis and promote breast cancer progression

Background Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The transcription factor SALL2 has been shown to play distinct roles in tumorigenesis and progression, but its specific role in BRCA remains unclear. Therefore, this study investigates the effects of SALL2 on BRCA progression.Methods SALL2 expression in the TCGA and clinical BRCA tissue samples was analyzed. Cell and animal models were established to validate the effects of SALL2 on BRCA cell proliferation, migration, and tumorigenicity. Molecular experiments were performed to investigate the association between NSUN2 and SALL2 in BRCA and cellular ferroptosis regulation by SALL2.Results SALL2 is significantly overexpressed in BRCA tissues and cell lines, knocking down SALL2 reduces BRCA cell growth, migration, and tumorigenesis in vitro and in vivo models. The m5C methyltransferase NSUN2, together with the reader protein YBX1, modifies SALL2 mRNA with m5C, which stabilizes the transcript. SALL2 then acts as a transcriptional repressor by binding directly to the promoter region of ACSL4 and inhibiting its transcriptional activity. Suppression of SALL2 activates ferroptotic cell death by lowering the antioxidant defences of GPX4/SLC7A11 and increasing the expression of ACSL4 and COX2. Ferroptosis inhibitors can reverse the growth-inhibiting effects caused by SALL2 depletion.Conclusion In BRCA, SALL2 is precisely regulated by m5C RNA methylation modification, further promoting cancer progression by inhibiting cell ferroptosis, suggesting its potential as a prognostic biomarker and a target for therapy.