What question did this study set out to answer?

The research aims to explore how transforming growth factor-beta3 affects heart function during sepsis by altering cellular metabolism.

January 10, 2026Molecular and Cellular Biochemistry0 citationsOpen Access

Transforming growth factor-β3 attenuates septic cardiomyopathy by reversing cardiomyocyte metabolic reprogramming through Smad7 signaling

HZHongxuan ZhangFujian Medical University JXJingqing XuFujian Medical University BXBing XuFujian Medical University

Key Points

The research aims to explore how transforming growth factor-beta3 affects heart function during sepsis by altering cellular metabolism.
Utilized animal models of sepsis to evaluate cardiac function.

Structured PICO

Does TGF-β3 improve septic cardiomyopathy by reversing metabolic reprogramming in rat models?

Population

8-week-old male SD rats (in vivo cecal ligation and puncture model of sepsis) and primary rat cardiomyocytes (in vitro lipopolysaccharide stimulation model)

Intervention

Myocardial injection of TGF-β3-overexpressing or interfering adenovirus (in vivo); TGF-β3 overexpression plasmid (in vitro)

Comparator

Sham operation (in vivo), empty vector (in vitro), and unmodulated septic cardiomyopathy model

Outcome

Myocardial injury (assessed by H&E staining, TUNEL assay, and transmission electron microscopy) and metabolic reprogramming (extracellular acidification rate and oxygen consumption rate)surrogate

TGF-β3 confers cardioprotection in septic cardiomyopathy by reversing metabolic reprogramming through the Smad7/SKP1 axis, representing a potential novel therapeutic target.

Abstract

Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although transforming growth factor-β3(TGF-β3) modulates energy metabolism in other tissues, its function in SCM pathogenesis remains unexplored. In vivo, cecal ligation puncture (CLP) rat models received myocardial injections of TGF-β3-overexpressing or interfering adenovirus. Myocardial injury through histopathology (H oxygen consumption rate, OCR). Molecular mechanisms were investigated via Western blotting and co-immunoprecipitation (Co-IP) targeting TGF-β3/Smad7/SKP1 signaling. 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. 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.

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