Abstract: In the present invention, the proteomic identification of HBc interacting factors in the nucleus of human hepatocytes revealed a majority of RNA-binding proteins (RBPs) intervening in mRNA metabolism and especially, the serine/arginine-rich splicing factor (10) (SRSF1O) which was found enriched nearly (3000) times in HBc complexes. Inventors demonstrated that the inhibition of SRSF1O phosphorylation with the small molecule 1C8 (4-pyridinonebenzisothiazole carboxamide) induces a strong inhibition of HBV replication (genotypes C and D) in persistently-infected hepatocytes, as well as to a strong inhibition of the establishment of HBV cccDNA in de novo infection settings. Accordingly the present invention relates to an inhibitor of SRSF1O activity for use in the treatment of Hepatitis B virus (HBV) infection said inhibitor maintain SRSF1O in a dephosphorylated state and prevents or reduces the splicing activity of SRSF1O.