USP13-Mediated selective autophagy of eIF5B promotes pathological cardiac hypertrophy.

Pathological cardiac hypertrophy and heart failure pose significant global health challenges. Maintaining cardiomyocyte homeostasis is crucial for slowing disease progression. Our findings reveal that Ubiquitin-specific peptidase 13 (USP13), a key component of the Protein Quality Control (PQC) system and a deubiquitinase highly expressed in cardiac tissue, is significantly upregulated in both human and experimental models of pathological cardiac hypertrophy and heart failure. Comprehensive in vivo and in vitro studies demonstrate that USP13 overexpression accelerates the progression of pathological cardiac hypertrophy and heart failure, whereas genetic silencing of USP13 in vitro mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy. Mechanistically, as shown by immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (co-IP), and immunofluorescence analysis, USP13 promotes the interaction between eukaryotic translation initiation factor 5B (eIF5B) and the autophagy receptor SQSTM1/P62, directing eIF5B to selective autophagic degradation. This process leads to eIF5B depletion, which exacerbates pathological cardiac hypertrophy and heart failure while counteracting the protective effects of USP13 silencing. This study is the first to elucidate the pivotal role of the USP13-eIF5B axis in pathological cardiac hypertrophy and heart failure, shedding light on the molecular mechanisms and identifying a promising therapeutic target in human end-stage heart failure.