Yang Tongwang, Gu Zhiyun, Feng Juan, Shan Juanjuan, Qian Cheng, Zhuang Na
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China.
Front Immunol. 2025 Jun 11;16:1576739. doi: 10.3389/fimmu.2025.1576739. eCollection 2025.
Non-neoplastic chronic liver diseases (CLDs), including alcoholic liver disease, metabolic-associated fatty liver disease, viral hepatitis, fibrosis, and cirrhosis, pose a global health challenge due to progressive fibro-inflammatory remodeling. Emerging evidence highlights the pivotal roles of non-parenchymal cells (NPCs)-liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KCs), and innate immune lymphocytes such as natural killer (NK) and natural killer T (NKT) cells-in driving disease progression. Chronic liver injury triggers LSEC capillarization, HSC transdifferentiation into collagen-producing myofibroblasts, and KC polarization toward pro-inflammatory phenotypes, collectively exacerbating extracellular matrix deposition and immune dysregulation. Dysfunctional NK/NKT cells play dual roles in antiviral defense and fibrosis amplification through excessive cytokine production. This review summarizes recent advances in understanding NPC-driven mechanisms underlying chronic liver injury and fibrosis, with a focus on LSEC dysfunction, HSC activation, and inflammation mediated by KCs and NK/NKT cells. Furthermore, we delve into emerging therapeutic strategies aimed at targeting NPC-specific pathways, including mechanotransduction modulation in LSECs, metabolic reprogramming of HSCs, and regulation of KC polarization. These approaches provide valuable insights into halting CLD progression and advancing the development of innovative antifibrotic therapies.
非肿瘤性慢性肝病（CLD），包括酒精性肝病、代谢相关脂肪性肝病、病毒性肝炎、肝纤维化和肝硬化，由于进行性纤维炎症重塑，对全球健康构成挑战。新出现的证据突出了非实质细胞（NPC）——肝窦内皮细胞（LSEC）、肝星状细胞（HSC）、库普弗细胞（KC）以及天然杀伤（NK）细胞和自然杀伤T（NKT）细胞等固有免疫淋巴细胞——在推动疾病进展中的关键作用。慢性肝损伤会引发LSEC毛细血管化、HSC向产生胶原蛋白的肌成纤维细胞转分化以及KC向促炎表型极化，共同加剧细胞外基质沉积和免疫失调。功能失调的NK/NKT细胞通过过度产生细胞因子在抗病毒防御和纤维化放大中发挥双重作用。本综述总结了在理解NPC驱动的慢性肝损伤和纤维化潜在机制方面的最新进展，重点关注LSEC功能障碍、HSC激活以及由KC和NK/NKT细胞介导的炎症。此外，我们深入探讨了旨在靶向NPC特异性途径的新兴治疗策略，包括LSEC中的机械转导调节、HSC的代谢重编程以及KC极化的调节。这些方法为阻止CLD进展和推进创新抗纤维化疗法的开发提供了有价值的见解。
