Urolithin A ameliorates HFpEF cardiac remodeling in mice by activating AMPK and inhibiting mTOR to restore mitophagic flux, while simultaneously remodeling the gut microbiome-ceramide axis to reduce lipotoxic stress.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse (HFpEF two-hit model) |
| Journal | Experimental and Molecular Medicine |
| Year | 2026 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/s12276-026-01776-2 · PMID 42432192 |
In a two-hit HFpEF mouse model (high-fat diet + L-NAME), urolithin A (UA) alleviated diastolic dysfunction, cardiac hypertrophy, and fibrosis. UA activated AMPK signaling while inhibiting mTOR, promoting ULK1-dependent autophagy initiation and restoring impaired mitophagic flux. Multi-omics revealed UA remodels the gut microbiome-ceramide axis, reducing circulating ceramide accumulation and lipotoxic stress. Single-nucleus transcriptomics in human iPSC-derived cardiomyocytes confirmed attenuation of fibrosis-related cellular programming.
| Intervention | Urolithin A (gut microbiome-derived compound) |
| Target | AMPK / mTOR / ULK1 / mitophagy / ceramide axis |
| Model | Mouse |
| Effect | Improved diastolic function, reduced cardiac hypertrophy and fibrosis via mitophagy restoration; reduced ceramide accumulation |