Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [ChIP-seq]
We applied Tet2?/? bone marrow transplantation (BMT) mouse model to investigate the contribution of clonal hematopoiesis to cardiac aging. A transcriptome-guided small-molecule screening strategy was employed to identify potential therapeutic compounds. Target validation involved molecular docking, enzymatic inhibition, and surface plasmon resonance assays. Epigenetic regulation was assessed using chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptomic profiling.  Genetic and pharmacological perturbation experiments were conducted to examine pathway involvement.Genetic manipulation confirmed the KDM5C–SIRT2–SASP regulatory axis mediates oridonin's effects.TET2-driven clonal hematopoiesis promotes cardiac aging via inflammatory and epigenetic pathways. These finding point that oridonin, as a novel epigenetic modulator, attenuates myocardial dysfunction by inhibiting the KDM5C–SIRT2–SASP axis, supporting its potential as a targeted therapeutic candidate for CHIP-associated cardiac aging. Overall design: ChIP-seq profiling was performed on bone marrow-derived macrophages(BMDMs) from Tet2-deficient mice 12 months after bone marrow transplantation and treatment with Oridonin 2 months. ChIP-seq of the histone modification H3K4me3 in BMDMs.