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

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Molecular Mechanisms of Disease

Background:

• Cardiac fibrosis, driven by fibroblast activation, impairs heart function and leads to heart failure.
• Folliculin (FLCN), known for roles in cellular processes, has been linked to severe heart failure in knockout models.
• Inhibition of cardiac fibrosis is a key therapeutic strategy for cardiac diseases.

Purpose of the Study:

• To investigate the role of Folliculin (FLCN) in cardiac fibrosis.
• To elucidate the underlying mechanisms of FLCN's action in cardiac fibroblasts.
• To explore FLCN and YTHDF3 as potential therapeutic targets for myocardial fibrosis.

Main Methods:

• Transverse aortic constriction (TAC) surgery in mice to induce cardiac fibrosis.
• In vitro studies using primary mouse cardiac fibroblasts treated with Ang-II.
• Analysis of FLCN protein and mRNA expression levels.
• Investigation of FLCN's interaction with cPLA2 and its effect on lysosomal function.
• Assessment of YTHDF3's role in FLCN mRNA methylation and its impact on cardiac fibrosis.

Main Results:

• FLCN expression was significantly decreased in TAC mice and Ang-II treated fibroblasts.
• FLCN overexpression inhibited lysosomal function and protected against TAC-induced cardiac fibrosis.
• FLCN interacted with cPLA2, enhancing its activity and improving lysosomal function.
• Reduced FLCN expression was linked to YTHDF3-regulated m6A methylation of FLCN mRNA.
• YTHDF3 overexpression alleviated fibrosis, improved cardiac structure and function in TAC mice.

Conclusions:

• FLCN plays a protective role against cardiac fibrosis by regulating lysosomal function and interacting with cPLA2.
• YTHDF3-mediated m6A modification of FLCN mRNA influences its expression and contributes to cardiac fibrosis.
• FLCN and YTHDF3 represent potential therapeutic targets for treating cardiac fibroblast-mediated myocardial fibrosis.