Objective To investigate the effect and underlying mechanism of serine and arginine rich splicing factor 1(SRSF1)on the replication of hepatitis B virus(HBV).Methods The effects of SRSF1 on HBV replication were investigated in different HBV replicating cell models by Southern blotting,Northern blotting and ELISA.Quantitative PCR,luciferase reporter assay and chromatin immunoprecipitation(ChIP)were applied to determine the effects of SRSF1 on the activities of HBV core promoter/enhancer in HepG2 cells.The relationship between SRSF1 and P53 was explored with Western blotting and ubiquitination assay.The effects of P53 on HBV replication were verified in different HBV replicating cell models,and the role of P53 in SRSF1 inhibition of HBV was clarified.Results Overexpression of SRSF1 significantly inhibited HBV DNA and HBV RNA and reduced HBsAg and HBeAg secretion levels in a variety of HBV replicative cell models(P<0.0001).SRSF1 also inhibited the activity of HBV core promoter,although this inhibition was regulated by indirect mechanisms.In addition,SRSF1 enhanced P53 stability by protecting P53 from ubiquitination and subsequent proteasomal degradation.Meanwhile,the regulatory effect of overexpression or knockdown of P53 on HBV was validated in different cell models(P<0.0001).Conclusion Overexpression of splicing factor SRSF1 significantly inhibits HBV replication in a variety of cell models,and this inhibitory effect is mediated by its enhancement of P53 stability.