Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood and treatment options are limited. Here, we demonstrate that hepatic expression of Bone Morphogenetic Protein 8B (BMP8B), a member of the TGFβ/BMP superfamily, increases proportionally to disease stage in patients and animal models of NASH. BMP8B signals via both Smad 2/3 and Smad 1/5/9 branches of the TGFβ/BMP pathway in hepatic stellate cells (HSC), promoting their pro-inflammatory phenotype. Absence of Bmp8b prevents HSC activation, reduces inflammation, affects the wound healing responses, thereby limiting NASH progression. Specular evidences were obtained in primary human 3D micro-tissues modelling NASH when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Due to the near absence of BMP8B in healthy livers, inhibition of BMP8B might represent a promising new therapeutic avenue for NASH treatment. / MV, JLG, AVP are supported by MRC programs (MRC MDU Programme Grant. PO 4050281695 “Lipotoxicity and the Metabolic Syndrome” and MRC DMC MC UU 12012/2 to AVP; Lipid Profiling and Signalling, MC UP A90 1006 to JLG) and MRC adjunct funding as part of the Cambridge Initiative in Metabolic Diseases (Lipid Dynamics and Regulation: MC_PC_13030). MV, MA and AVP are also supported by the Cambridge NIHR Biomedical Research Center (Gastroenterology); MV is recipient of the BRC Gastroenterology Pump-Priming award 2018/2019 that founded part of this study. FO is supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. JL is supported by Medical Research Council PhD studentship and a CRUK program grant (C18342/A23390). QMA, MV, AVP, VR, MA and DT are contributing members of the European NAFLD Registry. QMA is supported by the Newcastle NIHR Biomedical Research Centre (BRC). MV has been fellow of the Fondazione Umberto Veronesi in 2014. MA, AVP, and JLG received funding from the Evelyn Trust. MV, OG, DT, MA, FO, QMA, MJN DJL, and AVP are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413.