Key result
RNF123 deficiency mitigates cardiac hypertrophy and dysfunction in mice by preserving PRDX1 and reducing oxidative stress.
Why the study?
Pathological cardiac hypertrophy is a key risk factor for heart failure, and illustrating its pathogenesis and the critical role of protein ubiquitination may contribute to treatment.
RNF123 mediates pathological cardiac hypertrophy by ubiquitinating PRDX1 and increasing oxidative stress, identifying it as a potential therapeutic target for heart failure.
RNF123 inhibition may merit further preclinical testing in HF; leaves open its therapeutic potential in patients.
Background Pathological cardiac hypertrophy is a key risk factor for heart failure (HF). Illustrating the pathogenesis of cardiac hypertrophy may contribute to the treatment of HF. Studies have emphasized that protein ubiquitination is a critical event in HF. In this study, we investigated the role of an E3 ubiquitin ligase, RNF123, in HF induced by angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) surgery. Methods Heart failure was induced by Ang II infusion or TAC surgery in wild‐type and RNF123 knockout mice. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis combined with co‐immunoprecipitation (Co‐IP) was used to identify PRDX1 as an interacting protein of RNF123. Results The expression of RNF123 was significantly increased in cardiomyocytes of mice subjected to Ang II infusion or TAC surgery. RNF123 deficiency mitigated cardiac hypertrophy and dysfunction induced by Ang II infusion or TAC operation in mice. In vitro, RNF123 knockdown attenuated Ang II‐induced hypertrophy, whereas RNF123 overexpression exacerbated the pathological alterations in neonatal rat ventricular myocytes (NRVMs). Mechanistically, LC–MS/MS and Co‐IP assays revealed that RNF123 directly bound to the N‐terminal domain of PRDX1 and added a K48‐linked ubiquitin chain at the K7 site of PRDX1, subsequently facilitating PRDX1's proteasomal degradation. RNF123‐mediated degradation of PRDX1 increased the ROS level in cardiomyocytes, driving the pathogenesis of myocardial hypertrophy. Conclusions Our findings identified that cardiomyocyte RNF123 mediates pathological cardiac hypertrophy via ubiquitinating PRDX1 and highlighted that targeting RNF123 may represent a promising therapeutic strategy for HF.
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Wang et al. (2026) studied Pathological cardiac hypertrophy and heart failure. RNF123 knockout or knockdown vs. Wild-type or control was evaluated on Cardiac hypertrophy and dysfunction, PRDX1 degradation, and ROS levels. RNF123 deficiency mitigated cardiac hypertrophy and dysfunction in mice by preventing PRDX1 proteasomal degradation and reducing oxidative stress in cardiomyocytes.
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