N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) mitigates the liver fibrosis via WTAP/m6A/Ptch1 axis through Hedgehog pathway

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous tetrapeptide with potential antifibrotic effect. However, the underlying mechanism in the anti-fibrosis is still unclear. Here, we try to investigate its biofunction and deeplying mechanism in liver fibrosis. Rats were administrated with carbon tetrachloride (CCl4) for liver fibrosis model. The roles of AcSDKP on hepatic stellate cells (HSCs) were detected in vitro using isolated cells treated by TGF-β1. The m⁶A profie of HSCs was screened by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results demonstrated that AcSDKP inhibited apoptosis through Hedgehog pathway in the CCl₄-induced rat HSCs. Moreover, the administration of AcSDKP decreased the N⁶-methyladenosine (m⁶A) methyltransferase WTAP (Wilms' tumour 1-associated protein) expression. Mechanistically, WTAP targeted the 3'-UTR of Ptch1 mRNA, and administration of AcSDKP reduced the stability of Ptch1 mRNA. Thus, these findings revealed an anti-fibrosis axis of AcSDKP/WTAP/m⁶A/Ptch1 in liver fibrosis. Our results identify a novel role of AcSDKP in liver fibrosis via m⁶A modification and Hedgehog pathway, which helps us to shed light on the molecular mechanism in liver fibrosis progression.

Keywords: AcSDKP; Hedgehog pathway; Liver fibrosis; M(6)A; WTAP.