Background <p>Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. We aimed to explore the role of RNA binding motif protein 15 (RBM15) in high glucose (HG)-induced pyroptosis of renal tubular epithelial cell, thus providing theoretical knowledge and new targets for DN treatment.</p> Methods <p>HG-induced HK-2 cells were used to establish DN cell models. RBM15 expression was inhibited in HK-2 and detected. Cell viability was detected by cell counting kit-8. The levels of NLR family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4), gasdermin D (GSDMD)-N, and cleaved Caspase-1 were detected by Western blot assay. The levels of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. The enrichment of insulin-like growth factor 2 mRNA binding protein (IGF2BP2) and N6-methyladenosine (m6A) on NLRP3 and NLRC4 were analyzed by methylated RNA immunoprecipitation (MeRIP) and RIP. The stability of NLRP3 and NLRC4 mRNA was analyzed. The mechanism was verified by interfering NLRP3 and NLRC4 expression.</p> Results <p>RBM15 was highly expressed in HG-induced HK-2 cells. Inhibition of RBM15 reversed cell viability, inhibited inflammation, and alleviated pyroptosis. RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification.</p> Conclusion <p>RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification, thereby promoting pyroptosis.</p>