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

Hongxuan Zhang, Jingqing Xu, Bing Xu, Xiuling Shang

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In one paragraph

Article in Molecular and cellular biochemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 authors.

Hongxuan Zhang *Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, No. 134 East Street, Fuzhou, Fujian, China.

Jingqing Xu *Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, No. 134 East Street, Fuzhou, Fujian, China.

Bing XuDepartment of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, No. 134 East Street, Fuzhou, Fujian, China.

Xiuling ShangDepartment of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, No. 134 East Street, Fuzhou, Fujian, China. zksxling@163.com.

Funding

Fujian Provincial Health Technology Project No.2023ZQNZD001

6 · The paper itself

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&E) 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. 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.

Indexed as

CardiomyopathiesMyocytes, CardiacSepsisSignal TransductionSmad7 ProteinTransforming Growth Factor beta3AnimalsMaleMetabolic ReprogrammingRatsRats, Sprague-DawleySmad7 ProteinSmad7 protein, ratTransforming Growth Factor beta3Metabolic reprogrammingSeptic cardiomyopathySmad7TGF-β3

Identifiers

PMID41483124

DOI10.1007/s11010-025-05468-9

PMCPMC12996024

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LicenceCC BY-NC-ND

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.