Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro mechanistic study without human clinical trial data
PubMed 42432192 · doi:10.1038/s12276-026-01776-2
What was done
Researchers evaluated the therapeutic effects of the gut microbiome-derived metabolite urolithin A (UA) in a two-hit mouse model of heart failure with preserved ejection fraction (HFpEF) induced by a high-fat diet and Nω-nitro-L-arginine methyl ester. They performed in vivo assessments, multi-omics profiling (including gut microbiome and ceramide analysis), in vitro assays examining mitochondrial respiration and the AMPK-mTOR-ULK1 mitophagy pathway, and single-nucleus transcriptomic analyses in human induced pluripotent stem cell-derived cardiomyocytes.
What was found
The abstract reports qualitative outcomes without numerical data or effect sizes. UA alleviated diastolic dysfunction, cardiac hypertrophy, and myocardial fibrosis in HFpEF mice while restoring mitochondrial ultrastructure, respiration, and glycolytic capacity. Mechanistically, UA activated AMPK, inhibited mTOR, promoted ULK1-dependent autophagy, and restored mitophagic flux. UA also remodeled the gut microbiome, reduced circulating ceramides, and attenuated fibrosis-related transcriptomic programs in human cardiomyocytes.
Why it matters
HFpEF lacks effective disease-modifying therapies targeting underlying mitochondrial and metabolic defects. This study identifies a dual mechanism whereby urolithin A restores cardiac mitophagy and modulates the gut-ceramide axis to mitigate lipotoxicity and cardiac remodeling in preclinical models.
Limits
Evidence is entirely preclinical, relying on an animal model and cell culture systems, which may not fully replicate human HFpEF pathology. The abstract reports no quantitative values, effect sizes, dosages, treatment duration, or animal sample sizes.
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