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 transforming growth factor beta (TGFβ)–BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ–BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.

非酒精性脂肪性肝炎 (NASH) 的特点是脂毒性、炎症和纤维化，最终导致终末期肝病。促进 NASH 的分子机制知之甚少，治疗选择有限。在这里，我们证明骨形态发生蛋白 8B (BMP8B) 是转化生长因子 β (TGFβ)–BMP 超家族成员的肝脏表达，在患有 NASH 的人和动物模型中与疾病阶段成比例增加。BMP8B 通过肝星状细胞 (HSC) 中 TGFβ-BMP 通路的 SMAD2/3 和 SMAD1/5/9 分支发出信号，促进其促炎表型。在体内，缺乏 BMP8B 可防止 HSC 活化、减少炎症并影响伤口愈合反应，从而限制 NASH 进展。证据在原始人类 3D 微组织建模 NASH 中具有特色，当用重组 BMP8 攻击时。我们的数据显示 BMP8B 是 NASH 进展的主要贡献者。由于健康肝脏中几乎不存在 BMP8B，抑制 BMP8B 可能代表 NASH 治疗的有希望的新治疗途径。