PAD4 and Its Inhibitors in Cancer Progression and Prognosis.

The systemic spread of malignancies and the risk of cancer-associated thrombosis are major clinical challenges in cancer therapy worldwide. As an important post-translational modification enzyme, peptidyl arginine deiminase 4 (PAD4) could mediate the citrullination of protein in different components (including nucleus and cytoplasm, etc.) of a variety of cells (tumor cells, neutrophils, macrophages, etc.), thus participating in gene regulation, neutrophil extracellular trap (NET) and macrophage extracellular trap (MET). Thereby, PAD4 plays an important role in enhancing the growth of primary tumors and facilitating the distant metastasis of cancer cells. In addition, it is related to the formation of cancer-associated thrombosis. Therefore, the development of PAD4-specific inhibitors may be a promising strategy for treating cancer, and it may improve patient prognosis. In this review, we describe PAD4 involvement in gene regulation, protein citrullination, and NET formation. We also discuss its potential role in cancer and cancer-associated thrombosis, and we summarize the development and application of PAD4 inhibitors.