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

. 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.