TRIM47, stabilized by YTHDF3-mediated m6A modification, promotes cardiac lipid accumulation and aggravates diabetic...

Diabetic cardiomyopathy (DCM) is a prevalent and severe cardiovascular complication of diabetes mellitus, characterized by progressive cardiac dysfunction and pathological remodeling driven by myocardial metabolic disturbances. However, the underlying molecular mechanisms remain incompletely elucidated.

A type 2 DCM mouse model was established by feeding C57BL/6 mice a high-fat diet combined with streptozotocin injections. Cardiomyocyte-specific TRIM47 knockdown was achieved via AAV9-mediated delivery of a cardiomyocyte-specific cTnT promoter-driven shRNA. In vitro, primary neonatal mouse ventricular cardiomyocytes (NMCMs) were treated with palmitic acid (PA) to model cardiomyocyte injury.

TRIM47 was significantly upregulated in diabetic hearts. Cardiomyocyte-specific TRIM47 knockdown improved left ventricular ejection fraction and fractional shortening, attenuated chamber dilation, and reduced heart weight-to-tibia length ratio. TRIM47 silencing attenuated cardiomyocyte hypertrophy, interstitial fibrosis, and cardiomyocyte apoptosis, alongside reduced myocardial inflammatory cytokine levels (TNF-α, IL-6, IL-1β). Furthermore, TRIM47 knockdown alleviated myocardial lipid accumulation and reduced triglyceride levels, accompanied by downregulation of the fatty acid translocase CD36. In vitro, PA-treated NMCMs exhibited elevated TRIM47 expression, and its knockdown mitigated PA-induced cardiomyocyte injury, inflammation, apoptosis, and lipid deposition. Mechanistically, the m6A reader YTHDF3 was upregulated under PA conditions and directly bound to m6A-modified TRIM47 mRNA, enhancing its stability. Rescue experiments demonstrated that YTHDF3 overexpression exacerbated PA-induced cardiomyocyte injury, whereas concurrent TRIM47 knockdown largely reversed these deleterious effects.

Our results revealed that TRIM47 may contribute to the progression of DCM by promoting abnormal cardiac lipid metabolism, exacerbating inflammation and apoptosis, and these effects are partially mediated through the upstream m6A reader YTHDF3.