Schwabe Robert F, Brenner David A
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
Columbia University Digestive and Liver Disease Research Center, New York, NY, USA.
Nat Rev Gastroenterol Hepatol. 2025 May 22. doi: 10.1038/s41575-025-01068-6.
In the past decades, the pathogenic role of hepatic stellate cells (HSCs) in the development of liver fibrosis and its complications has been deeply characterized, rendering HSCs a primary target for antifibrotic therapies. By contrast, the beneficial roles of HSCs in liver homeostasis and liver disease are only beginning to emerge, revealing critical regulatory and fibrosis-independent functions in hepatic zonation, metabolism, injury, regeneration and non-parenchymal cell identity. Here, we review how HSC mediators, such as R-spondin 3, hepatocyte growth factor and bone morphogenetic proteins, regulate critical and homeostatic liver functions in health and disease via cognate receptors in hepatocytes, Kupffer cells and endothelial cells. We highlight how the balance shifts from protective towards fibropathogenic HSC mediators during the progression of chronic liver disease (CLD) and the impact of this shifted balance on patient outcomes. Notably, the protective roles of HSCs are not accounted for in current therapeutic concepts for CLD. We discuss the concept that reverting the HSC balance from fibrogenesis towards hepatoprotection might represent a novel holistic treatment approach to inhibit fibrogenesis and restore epithelial health in CLD simultaneously.
在过去几十年中，肝星状细胞（HSCs）在肝纤维化及其并发症发展中的致病作用已得到深入研究，这使得HSCs成为抗纤维化治疗的主要靶点。相比之下，HSCs在肝脏内环境稳态和肝脏疾病中的有益作用才刚刚开始显现，揭示了其在肝小叶分区、代谢、损伤、再生和非实质细胞特性方面的关键调节功能和与纤维化无关的功能。在此，我们综述了R-spondin 3、肝细胞生长因子和骨形态发生蛋白等HSC介质如何通过肝细胞、库普弗细胞和内皮细胞中的同源受体调节健康和疾病状态下肝脏的关键及稳态功能。我们强调了在慢性肝病（CLD）进展过程中，平衡如何从保护性HSC介质向促纤维化介质转变，以及这种平衡转变对患者预后的影响。值得注意的是，目前CLD的治疗理念并未考虑到HSCs的保护作用。我们讨论了将HSC平衡从纤维化转变为肝脏保护的概念，这可能代表一种新的整体治疗方法，可同时抑制CLD中的纤维化并恢复上皮健康。
