Inulin- and Butyrate-Mediated HIF-1α Butyrylation Prevent Diabetic Ferroptosis and Cardiomyopathy by Maintaining Iron Homeostasis.

Dysregulated iron metabolism and ferroptosis contribute to diabetic cardiomyopathy (DCM); however, the regulatory mechanisms and effective therapeutic strategies remain elusive. We sought to identify the role of hypoxia-inducible factor 1α (HIF-1α) in regulating myocardial iron homeostasis and ferroptosis in DCM, as well as evaluate the preventive effects of inulin on ferroptosis-induced DCM and elucidate its mechanism. Inulin-fermented butyrate activates the HIF-1α-ferritin heavy chain (FTH)/mitochondrial ferritin (FTMT) axis, alleviating cardiac ferroptosis and DCM, and stabilizes HIF-1α by promoting K190 Kbu modification and inhibiting ubiquitin-dependent degradation. Targeting the HIF-1α-FTH/FTMT axis via inulin, butyrate, or alternative approaches may represent a promising therapeutic strategy for alleviating DCM and other diabetes complications.