Ferroptotic vulnerability drives cardiac fibrosis and diastolic dysfunction in diabetic HFpEF via a gut-associated...

Diabetic heart failure with preserved ejection fraction (HFpEF) is a metabolically driven syndrome characterized by diastolic dysfunction and progressive myocardial fibrosis, yet the cellular mechanisms linking metabolic stress to fibroblast maladaptation remain poorly defined.

Using a high-fat diet combined with low-dose streptozotocin (HFD + STZ)-induced diabetic HFpEF mouse model, we observed significant hyperglycemia, insulin resistance, preserved ejection fraction, and marked diastolic dysfunction accompanied by severe myocardial fibrosis. Notably, diabetic HFpEF mice exhibited gut microbiota remodeling characterized by enrichment of Akkermansia muciniphila and elevated circulating L-proline levels. Broad-spectrum microbiota depletion alleviated cardiac fibrosis and diastolic impairment, whereas fecal microbiota transplantation from diabetic HFpEF donors recapitulated the pathological phenotype. Mechanistically, L-proline supplementation aggravated cardiac remodeling and induced ferroptotic cell death in cardiac fibroblasts, as indicated by decreased GPX4 and SLC7A11 and increased ACSL4 and TFR1 expression. Single-cell transcriptomic analysis revealed that proline-associated metabolic reprogramming preceded ferroptosis activation along the fibroblast trajectory under diabetic stress. Importantly, pharmacological inhibition of ferroptosis or fibroblast-specific activation of PPARγ signaling markedly attenuated myocardial fibrosis and improved diastolic function in diabetic HFpEF mice. Consistently, patients with diabetic HFpEF displayed increased A. muciniphila abundance and elevated serum L-proline levels, supporting translational relevance.

Our findings identify cardiac fibroblast ferroptotic vulnerability as a key pathogenic mechanism in diabetic HFpEF and uncover a gut microbiota-associated proline-PPARγ-ferroptosis axis that drives myocardial fibrosis and diastolic dysfunction under diabetic metabolic stress. These results highlight a metabolically driven fibroblast-centered mechanism and provide potential therapeutic targets for diabetic HFpEF.