Role of SERPINE1 (PAI-1) in gastric cancer: Molecular mechanisms, prognostic marker potential, and targeted therapeutic strategies.

Gastric cancer is one of the leading causes of cancer-related death worldwide, and therapeutic options for advanced gastric cancer remain extremely limited. Plasminogen activator inhibitor-1 (PAI-1), encoded by the SERPINE1 gene, serves as a pivotal oncogenic driver in gastric cancer, exerting both fibrinolytic-dependent and fibrinolytic-independent protumorigenic functions. This review systematically summarizes the molecular regulatory mechanisms underlying dysregulated SERPINE1/PAI-1 expression in gastric cancer, including transcriptional activation mediated by hypoxia-inducible factor-1α, nuclear factor-κB, transforming growth factor-β, as well as post-transcriptional regulation by non-coding RNAs and post-translational modifications of the protein. Furthermore, we elaborate the mechanisms by which PAI-1 promotes gastric cancer progression via enhancing cell proliferation, suppressing apoptosis, inducing angiogenesis, and mediating resistance to radiotherapy and chemotherapy. Notably, PAI-1 can shape an immunosuppressive tumor microenvironment by regulating immune cell polarization and programmed death-ligand 1 expression. Clinical studies have demonstrated that high PAI-1 expression is an independent prognostic biomarker associated with poor prognosis and aggressive pathological features in gastric cancer patients. This paper summarizes the latest advances in PAI-1-targeted therapy, including small-molecule inhibitors, neutralizing antibodies, and gene silencing strategies, and explores their synergistic potential in combination with chemotherapy and immunotherapy. Finally, we propose future research directions, including exploring the spatiotemporal expression heterogeneity of PAI-1 using omics technologies, establishing standardized detection methods, and developing highly selective PAI-1 inhibitors with low bleeding risk. This review clarifies the biological and clinical significance of PAI-1 in gastric cancer, providing a vital theoretical basis for the development of precise diagnosis and therapeutic strategies for gastric cancer.