Sharma Sachin, Prathigudupu Vijaya, Cable Carson, Serrano Lia R, Nerella Srilaxmi, Chen Alina, Hassan Ghmkin, Lakins Johnathon, Valenzuela Carlos Lizama, Tsukui Tatsuya, Ramamoorthi Roopa, Kim Jae-Jun, Willenbring Holger, Mattis Aras N, Volk Regan F, Zaro Balyn W, Coon Joshua J, Beresis Richard, DeGrado William F, Weaver Valerie M, Christenson Stephanie A, Jo Hyunil, Chen Jennifer Y
Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Sci Transl Med. 2025 Aug 27;17(813):eads9470. doi: 10.1126/scitranslmed.ads9470.
Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production, the possibility of promoting ECM degradation to resolve fibrosis remains largely untapped. The role of hepatic stellate cells (HSCs) in ECM degradation is an intriguing area for investigation. We previously demonstrated that inhibiting acid ceramidase (aCDase) increases ceramide in HSCs to ameliorate hepatic fibrosis. Here, we uncover a key signaling pathway that promotes ECM degradation in primary human HSCs, which is dependent upon the activation of protein kinase Cα (PKCα) and the induction of matrix metalloproteinase 1 (MMP-1) through extracellular signal-regulated kinase 1/2 (ERK1/2). Genetic reduction and pharmacological inhibition with a small molecule reduced aCDase activity, leading to increased collagen degradation and hepatic fibrosis resolution in the carbon tetrachloride (CCl) and fructose, palmitate, cholesterol, and trans-fat (FPC) mouse models. Consistently, ceramide signaling correlated with ECM remodeling and degradation in patients with metabolic dysfunction-associated steatotic liver disease. The findings show that ceramide regulates ECM degradation and establish aCDase as a target for therapeutic regression of fibrosis.
组织纤维化源于细胞外基质（ECM）成分的产生与分解之间的严重失衡。尽管目前的策略主要集中在抑制ECM的产生，但促进ECM降解以解决纤维化的可能性在很大程度上仍未得到开发。肝星状细胞（HSCs）在ECM降解中的作用是一个有趣的研究领域。我们之前证明，抑制酸性神经酰胺酶（aCDase）可增加HSCs中的神经酰胺，从而改善肝纤维化。在此，我们发现了一条促进原代人HSCs中ECM降解的关键信号通路，该通路依赖于蛋白激酶Cα（PKCα）的激活以及通过细胞外信号调节激酶1/2（ERK1/2）诱导基质金属蛋白酶1（MMP-1）。基因敲减和小分子药物抑制降低了aCDase活性，导致四氯化碳（CCl）和果糖、棕榈酸、胆固醇及反式脂肪（FPC）小鼠模型中的胶原降解增加和肝纤维化消退。同样，在代谢功能障碍相关脂肪性肝病患者中，神经酰胺信号与ECM重塑和降解相关。这些发现表明神经酰胺调节ECM降解，并将aCDase确立为纤维化治疗性消退的靶点。
