Therapeutic Targeting of Decr1 Ameliorates Cardiomyopathy by Suppressing Mitochondrial Fatty Acid Oxidation in Diabetic Mice.

Summary

Decr1 expression was consistently upregulated in diabetic cardiomyopathy. Cardiomyocyte-specific Decr1 knockdown preserved ejection fraction and fractional shortening and reduced hypertrophy, fibrosis, apoptosis, and oxidative damage, whereas overexpression aggravated disease. Mechanistically, Decr1 increased PDK4, leading to HDAC3 mitochondrial translocation and HADHA deacetylation, driving excessive FAO. Two natural products (Atranorin, Kurarinone) inhibited Decr1 and improved cardiac function in diabetic mice.

Key Findings

• Decr1 is upregulated in diabetic hearts and cardiomyocytes (+255% and +281%, p<0.0001).
• Cardiomyocyte-specific Decr1 knockdown improved EF (+41%) and FS (+24%) and reduced hypertrophy (−34%), fibrosis (−69%), apoptosis (−56%), and oxidative damage (−59%).
• Mechanism: Decr1 upregulates PDK4, inducing HDAC3 phosphorylation/mitochondrial translocation and HADHA deacetylation, driving excessive FAO.
• Overexpression of PDK4 abrogated the benefits of Decr1 downregulation in DCM mice.
• Natural products Atranorin and Kurarinone inhibited Decr1 and improved EF/FS in DCM.

Clinical Implications

While preclinical, targeting Decr1 or downstream PDK4/HDAC3 signaling could complement glucose-centric strategies in diabetic cardiomyopathy by curbing lipotoxic FAO. These findings motivate translational work toward first-in-human studies of Decr1 inhibitors.

Limitations

• Preclinical mouse and cell models; no human validation or long-term safety data.
• Natural inhibitors identified require optimization, PK/PD profiling, and off-target assessment.

Future Directions

Validate Decr1/PDK4/HDAC3/HADHA axis in human myocardial tissues, optimize small-molecule inhibitors, and test efficacy and safety in large-animal DCM models prior to early-phase clinical trials.