Work

4E-BP inhibition ameliorates heart failure through translational upregulation of SERCA2a and modulation of mitochondrial redox signaling in cardiomyocytes

Year: 2026

Type: article

Abstract: Reduced SERCA2a expression impairs cardiomyocyte contraction and relaxation, contributing to the progression of congestive heart failure (CHF). The translation of specific mRNAs, including SERCA2a, is suppressed by 4E-binding proteins (4E-BPs) through preventing the assembly of an intact initiation complex. Here, we investigated the role of 4E-BPs in regulating cardiac SERCA2a expression and transverse aortic constriction (TAC)-induced CHF in mice via genetic deletion of both 4E-BP1 and 4E-BP2 (4E-BP1/2 DKO), as well as through cardiac-specific knockdown or overexpression of 4E-BP1. 4E-BP1/2 DKO markedly alleviated TAC-induced CHF and mortality without affecting left ventricular hypertrophy. RNA-seq and mitochondrial respiratory analyses showed that 4E-BP1/2 DKO mitigated TAC-induced mitochondrial dysfunction and oxidative stress. Similar protective effects were observed with 4E-BP1 knockdown, whereas 4E-BP1 overexpression worsened these pathological changes. Mechanistically, 4E-BP1/2 DKO increased SERCA2a mRNA binding to eIF4G, thereby enhancing SERCA2a protein translation in the myocardium. Cardiac-specific Serca2a knockdown in TAC-challenged 4E-BP1/2 DKO mice reversed these protective effects. Consistent findings were obtained in a cardiomyocyte cell line. In summary, our results demonstrated that 4E-BP1/2 DKO translationally increased myocardial SERCA2a expression and rescued mice from CHF development after TAC, indicating that interventions reducing the signaling of cardiac 4E-BPs may be a novel therapeutic approach for treating CHF.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104089