The m6A modification of SOX18 leads to increased PTX3 and cardiomyocyte pyroptosis in sepsis-induced cardiomyopathy

Rationale: Sepsis-induced cardiomyopathy (SIC) is a rapidly progressing condition with poor prognosis in the absence of effective therapeutic interventions.Cardiomyocyte pyroptosis is a critical factor contributing to cardiac dysfunction in SIC.Currently, research on this mechanism remains unclear.Methods: We performed LPS-induced primary mouse cardiomyocyte modeling and mouse SIC modeling.Through mRNA-Seq, we found significant pyroptosis in the cardiac tissue of SIC mice.Further confocal microscopy and immunoprecipitation results confirmed that PTX3 is an important participant in cardiomyocyte pyroptosis.We then used ChIP and dual-luciferase reporter assays to confirm that SOX18 exerts a transcriptional repression effect on PTX3.M6A-Seq and RNA stability assays confirmed that the m6A modification mediated/recognized by RBM15/YTHDF2 is a crucial factor in the changes of SOX18 in SIC.Results: Our experiments demonstrated that the abnormally elevated PTX3 in SIC plays a key role in mediating pyroptosis.Under physiological conditions, PTX3 transcription is repressed by SOX18.However, during septic cardiomyopathy, SOX18 stability is compromised by RBM15/YTHDF2-mediated m6A modification, leading to increased PTX3 levels and the subsequent induction of cardiomyocyte pyroptosis. Conclusion:In summary, we have delineated the RBM15/YTHDF2-SOX18-PTX3 axis in SIC.It provides a new approach for the treatment of cardiomyocyte pyroptosis in SIC and for improving prognosis.