Hgs, also known as Hepatocyte growth factor-regulated tyrosine kinase substrate, is a vital element of the Endosomal sorting required for transport (ESCRT) pathway. This pathway mediates protein sorting for degradation and is crucial for maintaining protein homeostasis (proteostasis) [1].

Cardiomyocyte-specific Hgs gene knockout mice were generated to study its function. These knockout mice developed a phenotype similar to human restrictive cardiomyopathy (RCM). Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. It disrupted cholesterol transport and lysosomal integrity, leading to lysosomal storage disorder (LSD) with aberrant autophagosome accumulation and protein aggregation. Treatment with doxycycline to suppress protein aggregation attenuated cardiac fibrosis and diastolic dysfunction in Hgs-knockout mice [1].

In conclusion, Hgs plays a novel and important role in regulating cardiac lysosomal homeostasis and proteostasis. The use of Hgs gene knockout mouse models has uncovered its contribution to LSD-associated RCM-like cardiomyopathy, enhancing our understanding of the molecular mechanisms underlying this disease [1].