Walnut Peptides Alleviate Ferroptosis by Activating the Bile Acids-TGR5-DHHC4-CD36 Pathway and Glutathione Synthesis to Ameliorate Diabetic Cardiomyopathy

The incidence of diabetic cardiomyopathy (DbCM) is rising rapidly. Ferroptosis inhibition has emerged as a promising strategy for its treatment. New walnut peptides (WPs) were prepared to investigate their potential to ameliorate DbCM <i>via</i> ferroptosis inhibition in mice. WPs improved myocardial injury and cardiac dysfunction. Mechanistically, WPs promoted bile acid synthesis by activating CYP7A1, initiating the bile acids-TGR5-DHHC4-CD36 signaling cascade, which reduced FAs accumulation and peroxidation. WPs also supported glutathione synthesis by supplying amino acids, improving GPX4 activity, and then restoring cardiac redox balance. Fourteen anti-DbCM peptides were identified from WPs, characterized by continuous hydrophobic and acidic amino acid sequences. Five peptides containing these structural features demonstrated strong binding affinity for CYP7A1. In conclusion, WPs ameliorate DbCM by alleviating ferroptosis through the inhibition of FA accumulation/peroxidation. These findings validate the use of WPs as a functional food ingredient for FA metabolism regulation, providing a basis for adjunctive treatment in DbCM.