USP13 ameliorates myocardial infarction injury by inhibiting ferroptosis via stabilizing ALDOA.

Abstract

Despite the central role of deubiquitinases (DUBs) in maintaining protein homeostasis, their important role in post-myocardial infarction (MI) remodeling remains incompletely characterized. Our study identifies a DUB, ubiquitin-specific protease 13 (USP13), as a stress-responsive regulator exhibiting significant downregulation in MI-induced cardiac injury. USP13 deficiency aggravated cardiac ferroptosis and cardiac dysfunction after MI surgery. Mechanistically, USP13 directly bound to fructose-bisphosphate aldolase A (ALDOA) via its ubiquitin-specific protease domain. USP13 regulated K48-linked deubiquitination and the stability of ALDOA at K13, thereby preventing its degradation via the proteasomal pathway and restraining ferroptosis in cardiomyocytes. Moreover, specifical overexpression the endogenous USP13 in mouse hearts attenuated MI-induced cardiac injury. We confirmed that USP13 inhibited MI-induced cardiac injury by deubiquitinating and stabilizing ALDOA. These findings suggest that USP13 may serve as a promising therapeutic target for myocardial infarction, providing a foundation for developing novel treatment strategies focused on ferroptosis.