Key result
Elevated circulating TGF-β1 in cirrhosis promotes cardiac fibrosis by inhibiting Notch1 expression in cardiac fibroblasts through a DNMT3A/MeCP2-dependent DNA methylation mechanism.
Why the study?
Cardiovascular disease risk is elevated in patients with cirrhosis, but the underlying molecular mechanisms remain poorly understood.
Does cirrhosis-induced high TGF-β1 promote cardiac fibrosis via Notch1 inhibition?
Does cirrhosis-induced high TGF-β1 promote cardiac fibrosis via Notch1 inhibition?
This study identifies a novel molecular mechanism linking cirrhosis to cardiac fibrosis via TGF-β1-mediated epigenetic silencing of Notch1, offering potential therapeutic targets.
Answers are grounded in this paper and cite their sources.
May support TGF-β1/Notch1 targeting in cirrhotic cardiomyopathy; leaves open clinical validation in prospective studies.
Cardiovascular disease risk is elevated in patients with cirrhosis. However, the underlying molecular mechanisms remain poorly understood. Herein, we found that high levels of circulating transforming growth factor (TGF)-β1 were associated with an increased risk of cardiomyopathy in cirrhosis patients. Similarly, we confirmed that high circulating TGF-β1 elevated the progress of cardiac fibrosis in cirrhosis mice. Furthermore, elevated circulating TGF-β1 reduced Notch1 expression, increased glycolysis, promoted fibroblast proliferation and migration, and induced cardiac fibrosis. Interestingly, deletion of Notch1 exacerbated the progress of cardiac fibrosis in cirrhosis mice. Mechanistically, TGF-β1 elevated the DNA methylation levels in the Notch1 promoter by enhancing DNMT3A expression. Increased methylated CpGs then recruited the MeCP2 and suppressed Notch1 transcription. Reactivation of Notch1 through the knockdown of either DNMT3A or MeCP2 ameliorated glycolysis, proliferation, migration, and cardiac fibrosis in cardiac fibroblasts. Our study demonstrates that cirrhosis-induced high levels of circulating TGF-β1 increase the progress of cardiac fibrosis through the inhibition of Notch1 in a DNA methylation-dependent mechanism. These findings provide insights into the development of preventative measures for cirrhosis-induced cardiac fibrosis risk.
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Sun et al. (2025) studied Cirrhotic Cardiomyopathy (n=90). Elevated circulating TGF-β1 vs. Healthy controls and cirrhosis patients without cardiomyopathy was evaluated on Serum TGF-β1 levels (1.5-fold increase, p=0.001). Elevated circulating TGF-β1 in cirrhosis promotes cardiac fibrosis by inhibiting Notch1 expression in cardiac fibroblasts through a DNMT3A/MeCP2-dependent DNA methylation mechanism.
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