FASN-mediated de novo lipogenesis promotes ceramide accumulation and myocardial damage in arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a heritable disease caused by desmosomal gene mutations and marked by progressive myocardial loss and fibrofatty replacement. Here, we show that fatty acid synthase (FASN), the rate-limiting enzyme of de novo lipogenesis, is upregulated in cardiomyocytes of ACM patients and of a cardiomyocyte-specific Dsg2-mutant mouse model. Desmosomal dysfunction drives nuclear translocation of junction plakoglobin (JUP), which cooperates with SREBP1 to activate FASN transcription. The resulting de novo lipogenesis diverts glucose toward synthesis of lipotoxic ceramides, promoting cardiomyocyte apoptosis, as shown by isotope tracing, lipidomics, and RNA sequencing (RNA-seq). Pharmacological FASN inhibition with orlistat reduced myocardial lipid accumulation, apoptosis, inflammation, and fibrosis, improving cardiac function and survival. These findings define a JUP/SREBP1/FASN axis linking desmosomal dysfunction to myocardial lipotoxicity and identify FASN as a candidate therapeutic target in ACM.