SAE1 knockdown attenuates hepatic fibrosis by promoting ubiquitination and proteasomal degradation of TGF-β receptors.

Abstract

Objective: Liver fibrosis is characterised by excessive accumulation of extracellular matrix and can ultimately progress to cirrhosis and malignant transformation. Activation of hepatic stellate cells (HSCs), largely driven by transforming growth factor-beta (TGF-β) signalling, is a central event in fibrogenesis. SAE1 is a subunit of the small ubiquitin-like modifier-activating enzyme E1; its role in liver fibrosis and HSC activation remains unclear. This study aimed to investigate the regulatory function and underlying mechanism of SAE1 in hepatic fibrogenesis.

Methods: A carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis was established to assess SAE1 expression in vivo. SAE1 was silenced using an adeno-associated virus serotype 6-mediated approach. In vitro, primary HSCs and TGF-β-treated LX-2 cells were used to evaluate the effects of SAE1 knockdown on HSC activation and profibrotic gene expression. The activity of the TGF-β/SMAD signalling pathway and the stability of TGF-β receptors were also examined.

Results: SAE1 expression was significantly increased in fibrotic livers. SAE1 knockdown attenuated HSC activation and downregulated profibrotic genes. Mechanistically, SAE1 silencing promoted ubiquitin-proteasome-dependent degradation of TGF-β receptor I/II, thereby reducing SMAD2/3 phosphorylation. In vivo, Sae1 knockdown alleviated CCl₄-induced liver fibrosis.

Conclusion: SAE1 contributes to liver fibrosis by maintaining TGF-β receptor stability and enhancing TGF-β/SMAD-driven HSC activation. These results highlight SAE1 as a potential target for antifibrotic therapy.