JAK-STAT信号通路在肝纤维化中的研究进展

Research progress of JAK-STAT signaling pathway in liver fibrosis

摘要:

肝纤维化是慢性肝损伤后异常修复导致的病理过程，其核心机制涉及肝星状细胞（HSC）活化及细胞 外基质沉积。JAK-STAT信号通路通过调控炎症反应、免疫细胞极化和HSC功能，在肝纤维化中发挥双重作用。本 文系统综述了 STAT 家族（STAT1~6）在肝纤维化中的调控机制：STAT1 通过促进 NK 细胞杀伤活化的 HSC 和诱导 M1型巨噬细胞极化抑制纤维化；STAT2受长链非编码 RNA Fendrr调控，可能促进纤维化进展；STAT3作用具有争 议性，既可通过IL-6/STAT3/HIF轴加速HSC活化，又能维持NK细胞抗炎功能；STAT4和STAT6分别通过Th1/IFN-γ 和 Th2/IL-13 途径参与炎症相关纤维化；STAT5 则通过生长激素通路下调 TGF-β 发挥保护作用。目前靶向 JAKSTAT通路的药物（如STAT3抑制剂HJC0123、中药复方QRF等）已显示出抗纤维化潜力，表明该通路是肝纤维化治疗的重要靶点。深入解析STAT蛋白的协同与拮抗关系，将为开发精准抗纤维化策略提供新方向。

Abstract:

Liver fibrosis is a pathological process caused by aberrant repair following chronic liver injury, with its core mechanisms involving hepatic stellate cell (HSC) activation and excessive extracellular matrix (ECM) deposition. The JAK-STAT signaling pathway plays a dual role in liver fibrosis by regulating inflammatory responses, immune cell polarization, and HSC functions.This review systematically summarizes the regulatory roles of STAT family members (STAT1-6) in liver fibrosis: STAT1 exerts anti-fibrotic effects by promoting NK cell-mediated clearance of activated HSCs and inducing M1 macrophage polarization.STAT2, modulated by the long non-coding RNA Fendrr, may facilitate fibrotic progression.STAT3 exhibits context-dependent actions, driving HSC activation through the IL-6/STAT3/HIF-1α axis while preserving the anti-inflammatory capacity of NK cells. STAT4 and STAT6 promote inflammation-associated fibrosis via the Th1/IFN-γ and Th2/IL-13 pathways, respectively.STAT5 demonstrates protective effects by suppressing TGFβ signaling through growth hormone-dependent mechanisms.Currently, drugs targeting the JAK-STAT pathway (such as the STAT3 inhibitor HJC0123 and traditional Chinese medicine compound QRF) have demonstrated anti-fibrotic potential, highlighting this pathway as a crucial therapeutic target for liver fibrosis. A deeper understanding of the synergistic and antagonistic interactions among STAT proteins will provide novel directions for developing precise antifibrotic strategies.