Abstract

BACKGROUND:Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder and a leading cause of sudden cardiac death in young adults, exhibits substantial genetic and clinical heterogeneity. Although sarcomere gene sequence variations account for a major proportion of HCM cases, nearly half of patients lack identifiable genetic defects, implying the involvement of undiscovered mechanisms that may converge on a common pathogenic pathway. However, a unified molecular basis underlying HCM pathogenesis remains undefined.METHODS:We conducted an integrated analysis of hypertrophied interventricular septum tissues from 269 patients with obstructive HCM undergoing surgical myectomy. Targeted sarcomere gene screening, bulk RNA sequencing, and weighted gene coexpression network analysis were used to identify candidate drivers of disease. Cross-species validation was performed using a Myh6 R404Q/+ mouse model. Single-cell RNA sequencing delineated the cellular source of key factors, and biochemical assays and gain- and loss-of-function studies were used to assess their functional relevance. CRLF1 (cytokine receptor-like factor 1) emerged as a candidate mediator and was further evaluated in vitro and in vivo.RESULTS:CRLF1, predominantly secreted by activated cardiac fibroblasts, emerged as a key paracrine factor driving cardiomyocyte hypertrophy across patients with genetically heterogeneous HCM. CRLF1 levels were significantly elevated in hypertrophied myocardium and circulation. CRLF1 activated the LIFR (leukemia inhibitory factor receptor)–JAK1/2 (Janus kinase)–STAT3 (signal transducer and activator of transcription 3) signaling cascade to promote hypertrophy in both murine and human HCM models. Genetic ablation of Crlf1 in fibroblasts or pharmacological inhibition of its downstream pathway markedly attenuated disease phenotypes.CONCLUSIONS:Our findings uncover a common, nongenetic paracrine mechanism underlying HCM pathogenesis and establish CRLF1 as a prom