Cathepsin K as a key regulator of myocardial fibrosis in dilated cardiomyopathy and a promising therapeutic target.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure with a high mortality rate. Cardiac fibrosis plays a critical role in the progression of DCM, yet therapeutic strategies targeting fibrosis remain limited. Therefore, it is essential to investigate the underlying mechanisms of fibrosis in DCM. Our study demonstrates through the integration of weighted gene co-expression network analysis and gene ontology annotation that 35 biological processes, including cytokine production, were significantly associated with fibrosis in DCM. Protein-protein interaction analysis identified 82 crucial genes. The scRNA-seq identified cathepsin K (CTSK) as primarily expressed in cardiac fibroblasts. Masson's trichrome and immunofluorescence staining revealed that the level of fibrotic tissue in the left ventricle of patients with DCM and the expression of CTSK are higher than those in the normal ventricle. In vitro studies demonstrated that CTSK expression was upregulated in highly proliferative human cardiac fibroblasts (HCFs). PDGF-BB stimulation notably promoted HCF proliferation, an effect that was significantly attenuated by CTSK knockdown. However, CTSK depletion showed no inhibitory impact on TGF-β1-induced transdifferentiation of cardiac fibroblasts into myofibroblasts. Our research indicates that CTSK is a key regulator of myocardial fibrosis in DCM and is a promising therapeutic target.