YTHDF3-mediated FLCN/cPLA2 axis improves cardiac fibrosis via suppressing lysosomal function.

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Cardiac fibrosis characterized by aberrant activation of cardiac fibroblasts impairs cardiac contractile and diastolic functions, inducing the progression of the disease towards its terminal phase, resulting in the onset of heart failure. Therefore, the inhibition of cardiac fibrosis has become a promising treatment for cardiac diseases. The ovarian follicle-stimulating hormone folliculin (FLCN) plays a significant role in various biological processes, such as lysosome function, mitochondrial synthesis, angiogenesis, ciliogenesis and autophagy. Severe heart failure was observed in FLCN knockout mice. In this study, we investigated the role of FLCN in cardiac fibrosis and its potential mechanisms. The mice were subjected to transverse aortic constriction (TAC) surgery. Myocardial fibrosis developed in the mice 8 weeks after surgery. We showed that the protein and mRNA expression levels of FLCN were significantly decreased in TAC mice. Similar results were observed in primary mouse cardiac fibroblasts treated with Ang-II, an in vitro cardiac fibrosis model, suggesting that FLCN is involved in the pathological process of cardiac fibrosis. We demonstrated that overexpression of FLCN inhibited lysosome function in cardiac fibroblasts. Furthermore, overexpression of FLCN protected the heart from TAC-induced pathological cardiac fibrosis. We revealed that FLCN bound to the cPLA2 protein, increased its activity, regulated lysosomal function, and promoted membrane permeabilisation in cardiac fibroblasts during cardiac fibrosis. Knockdown of cPLA2 blocked the antifibrotic effect of FLCN in cardiac fibrosis. In addition, we found that the reduced expression of FLCN in cardiac fibrosis resulted from the modulation of YTHDF3-regulated m6A methylation of FLCN mRNA. The overexpression of YTHDF3 alleviated the production of collagens and improved cardiac structure and function in TAC mice. YTHDF3 inhibited proliferation and differentiation and regulated lysosomal function in mouse cardiac fibroblasts, whereas these effects were abolished by FLCN knockdown. We conclude that FLCN undergoes YTHDF3-regulated m6A modification and interacts with cPLA2 to improve lysosomal function in cardiac fibroblasts, highlighting its role in myocardial fibrosis therapy. These results suggest that FLCN and YTHDF3 could serve as potential therapeutic targets for cardiac fibroblast treatment.