Work

USP46 regulates glycolysis in the process of cardiac hypertrophy through the HIF-1α pathway

Year: 2025

Type: article

Abstract: Cardiac hypertrophy, a hallmark of various cardiovascular diseases, is characterized by metabolic reprogramming that leads to enhanced glycolytic activity. In the present study, we aimed to investigate the role of ubiquitin-specific protease46 (USP46) in regulating glycolysis of cardiac hypertrophy through the HIF-1α pathway. We provided evidence that USP46 was significantly elevated in hypertrophied mouse heart and in cell hypertrophy model, correlating with increased HIF-1α stability and activation of downstream glycolytic enzymes. We observed that knockdown of USP46 led to decreased HIF-1α levels and reduction in glycolysis rate, thereby attenuating myocardial hypertrophy in mice model of cardiac hypertrophy. Conversely, overexpression of USP46 enhanced the expression of HIF-1α, leading to increased glycolytic activity and exacerbation of cardiac hypertrophy. In vitro studies further demonstrated that USP46 enhances the stability of HIF-1α by binding to HIF-1α and reducing the ubiquitination of HIF-1α, thus promotes the transcriptional activity of HIF-1α, eventually facilitating the expression of metabolic genes associated with glycolysis. Metabolic profiling also confirmed that USP46/HIF-1α intervention significantly influenced lactate, pyruvate and ATP production in cardiac myocytes. Collectively, our findings suggest that USP46 plays a pivotal role in cardiac hypertrophy by modulating HIF-1α-dependent glycolytic processes. This study positions USP46 as a promising therapeutic target for the management of cardiac hypertrophy and related cardiovascular diseases, offering insights into the intricate interplay between deubiquitination, glycolysis, and cardiac remodeling.

Source: Pathology - Research and Practice

DOI: 10.1016/j.prp.2025.155980

Authors: Chunling Mu, Dahai Yu, Aixin Li, Yang Yu, Zhaoguang Liang

Institutions: First Affiliated Hospital of Harbin Medical University, Harbin University of Commerce, Harbin Medical University

Language: English

Topic: Ubiquitin and proteasome pathways

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,780