Fibrinogen superfamily proteins: Key regulators in hepatic disorders

Liver diseases including hepatic injury, hepatitis, metabolic-associated fatty liver disease, and hepatocellular carcinoma have emerged as critical public health challenges globally. The fibrinogen (FG) superfamily proteins, primarily comprising FG, FG-like protein (FGL) 1, and FGL2, have been demonstrated to exert regulatory effects on hepatic tissue regeneration, lipid metabolism homeostasis, and oncogenic processes in hepatocytes. This review systematically examines the pathophysiological correlations between FG superfamily members and major hepatic disorders. Physiologically, FG superfamily proteins function as hepatoprotective mediators through their intrinsic capacity to enhance hepatic parenchymal regeneration and extracellular matrix remodeling. However, emerging evidence reveals their dual regulatory properties, whereby overactivation of these hepatokines paradoxically induces a pathological shift characterized by pro-inflammatory cascades, metabolic derangement potentiation, and tumor invasion and metastasis promotion. Specifically, we elucidate the molecular mechanisms underlying their involvement in hepatitis progression, metabolic-associated fatty liver disease pathogenesis, and hepatocellular carcinoma tumorigenesis. Furthermore, we highlight their therapeutic potential in hepatic disease management, particularly emphasizing that targeting the FGL1/lymphocyte activation gene 3 immune checkpoint axis represents a novel paradigm in precision cancer immunotherapy.