Fabry disease is a monogenic disease characterized by a deficiency or loss of α-galactosidase A (GLA). Cardiomyopathy is the leading cause of death in Fabry patients
however, a lack of understanding of the pathological mechanism impedes the development of effective therapies. Here, we used a Gla knockout (KO) mouse model and investigated its impact on cardiomyopathy. We found that globotriaosylceramide (Gb3) increased the uptake and accumulation of fatty acids in KO hearts by increasing the expression levels of CD36 and ACC2. The augmented fatty acid metabolism further increased autophagy activity, leading to age-related late-onset cardiac hypertrophy. Additionally, increased autophagy facilitates disturbances in fatty acid metabolism. The inhibition of autophagy by supplementation with 3-methyladenine (3-MA) or the overexpression of GLA by the cardiomyocyte-specific adeno-associated virus for 2 months could rebalance abnormal fatty acid metabolism and ameliorate cardiac hypertrophy and dysfunction in KO hearts, suggesting a central role of autophagy in GLA deficiency-related cardiomyopathy.