Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [RNA-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. Genetic and pharmacological perturbation experiments were conducted to examine pathway involvement. Tet2⁺/⁻-BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Oridonin reversed CHIP- and aging-associated transcriptional signatures and attenuated cardiac remodeling. Mechanistically, oridonin inhibited KDM5C histone demethylase. Downregulation of the pro-senescent factor S100A8 and suppression of SASP-associated inflammation were observed. RNA-seq profiling was performed on cardiac tissues from wild-type and Tet2-deficient mice 12 months after bone marrow transplantation and treatment with Oridonin 2 months.

本研究采用Tet2⁺/⁻骨髓移植（bone marrow transplantation, BMT）小鼠模型，探究克隆性造血（clonal hematopoiesis）对心脏衰老的影响。本研究采用转录组导向的小分子筛选策略以鉴定潜在治疗性化合物，靶点验证涵盖分子对接、酶抑制实验及表面等离子体共振（surface plasmon resonance）检测。此外，本研究开展了遗传与药理学扰动实验以验证相关信号通路的参与性。结果显示，Tet2⁺/⁻骨髓移植小鼠呈现出随年龄进展的心肌纤维化、炎症反应、细胞衰老及心脏功能衰退。冬凌草甲素（Oridonin）可逆转与意义未明的克隆性造血（Clonal Hematopoiesis of Indeterminate Potential, CHIP）及衰老相关的转录特征，并减轻心脏重构。机制层面，冬凌草甲素可抑制KDM5C组蛋白去甲基化酶。研究同时观察到促衰老因子S100A8的表达下调，以及衰老相关分泌表型（senescence-associated secretory phenotype, SASP）相关炎症的缓解。本研究对骨髓移植12个月且经冬凌草甲素处理2个月的野生型与Tet2缺陷型小鼠的心脏组织开展了RNA测序（RNA-seq）转录组分析。