SRSF3 confers cuproptosis resistance in oral cancer by suppressing FDX1 expression

Cuproptosis, a novel copper-dependent form of regulatory cell death, represents a potential therapeutic strategy for cancer. However, copper-related anti-tumor treatment displayed limited efficacy and the mechanisms by which tumor cells develop resistance to cuproptosis remain poorly understood. In this study, we reported that oral squamous cell carcinoma (OSCC) cells exhibit enhanced resistance to cuproptosis compared with normal epithelial cells. We identified that this resistance is associated with low expression of ferredoxin 1 (FDX1), a key regulator of cuproptosis. RNA sequencing in copper-treated OSCC cells revealed significant alterations in RNA splicing pathways, with the serine and arginine rich splicing factor 3 (SRSF3) being markedly upregulated. Functional studies demonstrated that SRSF3 promotes cuproptosis resistance in both OSCC cells and normal epithelial cells, while its knockdown sensitizes OSCC cells to copper-induced death. Mechanistically, SRSF3 suppressed FDX1 and lipoic acid synthetase (LIAS) expression by decreasing their mRNA stability. Importantly, in syngeneic subcutaneous mouse model of OSCC, Srsf3 overexpression promoted tumor resistance to copper treatment, reflected by the reversion of copper-induced decrease in tumor growth and increase in CD8⁺ T cell infiltration in tumor. Our findings unveil a previously unrecognized mechanism of cuproptosis resistance, in which RNA binding protein SRSF3 destabilizes mRNAs of the key regulators of cuproptosis and highlight the potential of targeting SRSF3 to overcome copper tolerance in oral cancer therapy.