Hepatocyte growth factor alleviates alcoholic cardiomyopathy through the Nrf2 pathway-a focus on iron metabolism.

BACKGROUND

Alcohol misuse leads to cardiomyopathy. Hepatocyte growth factor (HGF) concentrations and iron metabolism fluctuations are both associated with cardiovascular diseases. This investigation is designed to test if and how HGF regulates cardiac ferroptosis.

METHODS

Male Sprague Dawley rats were used to establish animal models. Exogenous HGF's potential to reduce cardiomyocyte ferroptosis, which is typified by varying labile iron pool (LIP), elevated lipid peroxidation, and diminished cell survival, was examined by fluorescence quantification, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK8) and calcein staining. Nuclear factor erythroid 2-related factor 2 (Nfe2l2/Nrf2) was then screened by a public database as a potential target for HGF to block myocardial ferroptosis. Subsequently, Nfe2l2 knockdown was induced to verify Nrf2's mediating role for HGF's protection against myocardial ferroptosis, as well as HGF's particular effects on proteins involved in iron absorption, storage, and excretion.

RESULTS

HGF suppressed cardiac ferroptosis through Nfe2l2/Nrf2-related pathway, showing a decline in ferritin heavy chain 1 (FTH1) and an elevation in ferroportin (Fpn1) and divalent metal-ion transporter 1 (DMT1). Knockdown of Nfe2l2 reversed the protective effect against the promotion of lipid peroxidation and LIP in ethanol-induced cardiomyocytes, as well as changes in iron-related proteins.

CONCLUSIONS

HGF functions as a potent protective factor for alcoholic cardiomyopathy (ACM) by inhibiting cardiac ferroptosis via Nfe2l2/Nrf2-related pathway, and the effect is achieved by reducing iron storage while increasing iron exportation, thus lowering iron load in cardiomyocytes.