Authors
Hui Wang, Jieyu Cui, Chunlu Huang, Wanyi Guo, Tong Liu, Yi Zhu, Shuai Shao, Kangyin Chen, Jinlong He, Qiankun Bao
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77379. Aug 30, 2026. Epub Aug 30, 2026.
Abstract
Cardiac fibrosis is a central driver of adverse remodeling and heart failure (HF), yet effective antifibrotic therapies remain limited. SerpinA3, a member of the serine protease inhibitor family, has been implicated in cardiovascular disease, but its functional role and underlying mechanisms in cardiac remodeling are poorly defined.
Using a transverse aortic constriction (TAC) model, we observed that SerpinA3K expression was markedly reduced in failing mouse hearts and in circulation. Pharmacological supplementation or genetic augmentation of SerpinA3 markedly attenuated cardiac dysfunction and fibrotic remodeling in response to pressure overload. Single-cell transcriptomic analyses further demonstrated that SerpinA3 suppresses profibrotic fibroblast programs by promoting a transition from activated and extracellular matrix-producing fibroblasts toward a quiescent, pro-angiogenesis state. Mechanistically, SerpinA3 binds to the extracellular domain of TGF-beta receptor type-1, and disrupts TGF-β receptor type-1-TGF-β receptor type-2 complex formation, thereby preventing downstream Smad2/3 phosphorylation in cardiac fibroblasts.
SerpinA3 functions as an endogenous inhibitor of TGF-β signaling that restrains cardiac fibroblast activation and fibrotic remodeling. By targeting receptor complex assembly, SerpinA3 provides a selective mechanism to modulate profibrotic signaling. These findings identify SerpinA3 as a promising therapeutic target for HF associated with pathological fibrosis.
PMID:
42669162
Bibliographic data and abstract were imported from PubMed on 31 Aug 2026.
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