TGF-β3 attenuates septic cardiomyopathy by reversing cardiomyocyte metabolic reprogramming through Smad7 signaling

Abstract BACKGROUND Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although TGF-β3 modulates energy metabolism in other tissues, its function in SCM pathogenesis remains unexplored. METHODS In vivo, cecal ligation puncture (CLP) rat models received myocardial injections of TGF-β3-overexpressing or interfering adenovirus. Myocardial injury through histopathology (HE) and apoptosis (TUNEL), and mitochondrial ultrastructure via transmission electron microscopy (TEM). In vitro, primary cardiomyocytes treated with lipopolysaccharide (LPS) were transfected with TGF-β3 overexpression plasmid, with metabolic analyzed using Seahorse XF technology (extracellular acidification rate, ECAR; oxygen consumption rate, OCR). Molecular mechanisms were investigated via Western blotting and co-immunoprecipitation (Co-IP) targeting TGF-β3/Smad7/SKP1 signaling. FINDINGS TGF-β3 was significantly downregulated in SCM. Its overexpression attenuated myocardial injury and apoptosis, improved mitochondrial integrity, and reversed metabolic reprogramming by reducing glycolysis while enhancing OXPHOS. Mechanistically, TGF-β3 promoted Smad7 phosphorylation to inhibit Smad2/3 activation and suppressed SKP1 expression to reduce Smad7 ubiquitination, as confirmed by Co-IP. INTERPRETATION TGF-β3 confers cardioprotection in SCM by reversing metabolic reprogramming through dual regulation of Smad7: enhancing phosphorylation to block Smad2/3 signaling and inhibiting SKP1-mediated ubiquitination to stabilize Smad7. This newly identified TGF-β3/Smad7 axis represents a promising therapeutic target for SCM.