YTHDC2 promotes sepsis-induced cardiomyopathy by activating apoptosis and NF-κB pathway

Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, especially in children, and identification of novel therapeutic targets remains essential for improving patient outcomes. Recent studies have implicated N6-methyladenosine (m⁶A), an RNA epigenetic modification, in SICM pathogenesis. However, the role of YTH domain-containing 2 (YTHDC2), an m⁶A reader protein, in SICM remains unclear. This study used lipopolysaccharide (LPS)-treated adolescent rats, primary cardiomyocytes and H9c2 cardiomyocytes to mimic SICM <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. We observed a significant upregulation of YTHDC2 <i>in</i> <i>vivo</i> and <i>in</i> <i>vitro</i>. Through comprehensive analyses including RNA sequencing (RNA-seq), Western blotting, and flow cytometry, we demonstrated that YTHDC2 promotes LPS-induced cardiomyocyte apoptosis. RNA immunoprecipitation sequencing (RIP-seq) and Western blotting further showed that YTHDC2 activates the LPS-induced NF-κB pathway. Mechanistic investigations using RIP-qPCR confirmed direct binding of YTHDC2 to mRNAs encoding the pro-apoptotic proteins BAX and BAK1, as well as the NF-κB subunit p65, with subsequent regulation of NF-κB transcriptional activity. Importantly, adeno-associated virus 9 (AAV9)-mediated cardiac-specific inhibition of YTHDC2 in adolescent rats effectively attenuated LPS-induced cardiomyocyte apoptosis and NF-κB pathway activation. Collectively, our findings establish YTHDC2 as a key regulator in SICM pathogenesis, promoting cardiomyocyte apoptosis and NF-κB signaling activation. These results highlight YTHDC2 as a promising therapeutic target for SICM.