Data Sheet 1_Molecular mechanisms and therapeutic strategies of cGAS-STING pathway in liver disease: the quest continues.docx

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway has emerged as a central regulator of liver homeostasis and pathology, governing innate immunity, inflammation, fibrogenesis, and tissue repair. Dysregulated cGAS-STING signaling, often driven by cytosolic DNA sensing, cellular stress, or cross-activation with other immune pathways, leads to excessive type I interferons and pro-inflammatory cytokine production, exacerbating liver injury. This aberrant activation is implicated in chronic liver inflammation, fibrosis, and carcinogenesis, highlighting its dualistic role in both protective and pathogenic processes. This systematic review synthesizes current evidence on the context-dependent roles of the cGAS-STING pathway across liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), drug-induced liver injury (DILI), hepatic ischemia-reperfusion injury (HIRI), and parasitic infections. The cGAS-STING pathway exhibits dualistic functions in liver pathophysiology: while its activation promotes antiviral defense and tissue regeneration in acute injury, chronic hyperactivation drives inflammation, fibrosis, and oncogenesis. In NAFLD/ALD, metabolic stress and mitochondrial DNA leakage perpetuate STING-dependent inflammation, whereas in HCC, persistent signaling accelerates tumor progression and immune evasion. Similarly, in parasitic diseases or HIRI, cGAS-STING activation may enhance pathogen clearance or exacerbate tissue damage, depending on disease stage. Emerging therapeutic strategies, including STING inhibitors, agonists, and nano modulators, show promise in preclinical models but require context-specific optimization to balance beneficial immunity and pathologic outcomes. Understanding these context-dependent functions of cGAS-STING pathway provides critical insights for the development of targeted therapeutic strategies that may selectively modulate this pathway to treat diverse hepatic disorders.

环GMP-AMP合酶-干扰素基因刺激因子（cyclic GMP-AMP synthase–stimulator of interferon genes, cGAS-STING）通路已成为肝脏稳态与病理过程的核心调控通路，参与调控天然免疫、炎症反应、纤维化进程及组织修复。通常由胞质DNA感知、细胞应激或与其他免疫通路交叉激活所驱动的失调cGAS-STING信号转导，会导致过量I型干扰素与促炎细胞因子产生，进而加重肝脏损伤。这种异常激活与慢性肝脏炎症、纤维化及癌变密切相关，凸显了其在保护性与致病性过程中的双重作用。本系统综述整合了当前关于cGAS-STING通路在各类肝脏疾病中情境依赖性作用的研究证据，涵盖非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）、酒精性肝病（alcoholic liver disease, ALD）、病毒性肝炎、肝细胞癌（hepatocellular carcinoma, HCC）、药物性肝损伤（drug-induced liver injury, DILI）、肝缺血再灌注损伤（hepatic ischemia-reperfusion injury, HIRI）以及寄生虫感染。cGAS-STING通路在肝脏病理生理学中呈现双重功能：在急性损伤阶段，其激活可促进抗病毒防御与组织再生；而慢性过度激活则会引发炎症、纤维化及肿瘤发生。在非酒精性脂肪性肝病/酒精性肝病中，代谢应激与线粒体DNA泄漏会维持STING依赖的炎症反应；而在肝细胞癌中，持续的信号转导会加速肿瘤进展与免疫逃逸。同样，在寄生虫病或肝缺血再灌注损伤中，cGAS-STING的激活可促进病原体清除，或加重组织损伤，具体取决于疾病阶段。新兴的治疗策略包括STING抑制剂、激动剂与纳米调节剂，在临床前模型中已展现出潜力，但仍需针对具体情境进行优化，以平衡有益免疫与病理结局。阐明cGAS-STING通路的这种情境依赖性功能，可为开发靶向治疗策略提供关键见解，这些策略可选择性调控该通路以治疗多种肝脏疾病。