Oridonin as a novel KDM5C inhibitor alleviates clonal hematopoiesis-induced cardiac aging via H3K4me3-dependent SASP suppression

TET2-mediated clonal hematopoiesis of indeterminate potential (CHIP) is a known cardiovascular risk factor, but its role in cardiac aging and potential for pharmacological intervention remain unclear. Herein, Mendelian randomization using large-scale genome-wide association studies (GWAS) data assessed CHIP's causal impact on aging and cardiovascular disease that revealed significant causal associations between TET2-CHIP, CVD, and aging biomarkers. Transcriptome-guided screening identified oridonin as a candidate compound reversing CHIP- and aging-associated gene signatures. Multi-tiered target prediction combining chemical structure-based algorithms and transcriptomic correlation identified KDM5C as a key target, validated by enzymatic inhibition and surface plasmon resonance assays. In vivo and in vitro administration of oridonin significantly ameliorated cardiac dysfunction and pathological remodeling in the CHIP model. Epigenetic regulation was profiled via ChIP-seq and RNA-seq, focusing on H3K4me3-mediated transcription. Tet2 +/- BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Mechanistically, oridonin inhibited KDM5C histone demethylase, restored H3K4me3 levels, and activated the SIRT2 anti-aging pathway. Rescue experiments using gene overexpression and recombinant protein supplementation confirmed the functional role of the KDM5C-H3K4me3-SIRT2-S100A8 axis in mediating oridonin's effects. Overall, TET2-driven CHIP promotes cardiac aging, as evidenced by human genetic analyses and long-term BMT models. Oridonin, by inhibiting KDM5C and restoring H3K4me3-dependent SIRT2 signaling, mitigates CHIP-induced myocardial aging.