Research progress and clinical applications of SERPINE1 in liver diseases: a critical review

Shiyu Peng¹, Jie Gao², Jingyi Lu², Xinpei Luo², Zhui Ke^2*

¹Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University Xinshi District, Urumqi, Xinjiang Uygur Autonomous Region, China.

²Department of Oncology, The Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.

*Correspondence:

Zhui Ke; Email: kezhui1314@163.com

Abstract

SERPINE1 encodes plasminogen activator inhibitor-1 (PAI-1), a central inhibitor of tissue-type and urokinase-type plasminogen activators. By limiting plasmin generation, modulating extracellular-matrix turnover, and participating in inflammatory, metabolic, vascular, and tumor-microenvironmental processes, SERPINE1 is increasingly recognized as a context-dependent mediator in liver disease. Earlier versions of the literature often presented SERPINE1 as a uniformly pathogenic factor. A more balanced synthesis indicates that its effects depend on disease stage, cellular source, and biological context: hepatocyte- and adipose-associated PAI-1 may link metabolic stress to steatosis and insulin resistance; activated hepatic stellate cell-derived PAI-1 appears more directly related to fibrogenesis; endothelial and platelet-related PAI-1 may contribute to hypofibrinolysis and portal-vein thrombosis; and tumor- or stromal-derived PAI-1 may shape invasion, epithelial-mesenchymal transition, angiogenesis, and immune-cell recruitment in hepatocellular carcinoma. Clinical studies support an association between circulating PAI-1 and metabolic dysfunction-associated steatotic liver disease (MASLD), but most data are cross-sectional, heterogeneous, or derived from biomarker-discovery cohorts rather than definitive prospective validation. Therapeutically, PAI-1 inhibition has shown promise in cell, organoid, and animal models, particularly in steatosis and fibrotic remodeling; however, there is insufficient evidence to regard SERPINE1-targeted therapy as clinically established for liver diseases. This review critically summarizes the mechanistic, epidemiological, diagnostic, and therapeutic evidence for SERPINE1 in liver diseases, highlights unresolved controversies, and proposes a translational framework for future research.

Keywords: SERPINE1, PAI-1, MASLD, MASH, liver fibrosis, hepatocellular carcinoma, biomarker, targeted therapy