SYVN1-mediated succinate accumulation exacerbates heart failure.

Metabolic remodeling, defined as changes in the energy substrate preferences and energy production efficiency of the myocardium, is one of the pathogenic characteristics of failing hearts, though its molecular mechanisms remain incompletely understood. Through untargeted metabolomics coupled with targeted mass spectrometry, we report that plasma succinate levels are significantly elevated in patients with impaired cardiac function (ejection fraction, EF<50%) compared to those with preserved EF (EF⩾50%). Succinate is a key metabolite intermediate in the tricarboxylic acid cycle. Mechanistically, we demonstrate that β-adrenergic receptor activation upregulates synoviolin 1 (SYVN1), which promotes the ubiquitination and degradation of nuclear respiratory factor 1 (NRF1). In turn, this downregulates the expression of succinate dehydrogenase complex iron sulfur subunit B (SDHB), leading to intracellular succinate accumulation and subsequent release. Furthermore, we show that the sodium-glucose cotransporter 2 inhibitor empagliflozin binds to NRF1, restores SDHB expression, normalizes succinate levels, and ameliorates cardiac dysfunction in a pressure-overload model. Our findings delineate a novel SYVN1/NRF1/SDHB-succinate axis that drives mitochondrial dysfunction in heart failure, and identify its potential as a therapeutic target for metabolic modulation.