Padi2, short for peptidyl arginine deiminase 2, catalyzes the post-translational conversion of peptidyl-arginine to peptidyl-citrulline, a process called citrullination. This activity is involved in multiple biological processes such as transcriptional regulation, cell differentiation, and the immune response. Padi2-related pathways include MAPK, JAK2/STAT3, and those related to histone modification, which are crucial for maintaining normal cellular functions and are linked to various diseases [1,3,4,5].

In urothelial cancer, icaritin binds to and inhibits Padi2 expression in neutrophils, suppressing Padi2-mediated histone citrullination, ROS generation, and the MAPK signaling pathway, thus inhibiting neutrophil infiltration and NET-induced tumor metastasis [1].

In sepsis-induced acute lung injury, the deletion of Padi2 and Padi4 in double KO mice reduces Nlrp3+ pro-inflammatory macrophages and promotes the differentiation of Chil3+ myeloid cells into anti-inflammatory macrophages, enhancing the polarization of Ym1+ M2 macrophages by suppressing NLRP3, which aids in inflammation resolution and lung tissue repair [2].

In endometrial cancer, Padi2-catalyzed MEK1 citrullination activates ERK1/2, promotes IGF2BP1-mediated SOX2 mRNA stability, and supports the malignant state of EC. Gene silencing of Padi2 inhibits EC progression [3].

In prostate cancer, Padi2 is an androgen-repressed gene upregulated in CRPC. It promotes cell-cycle progression, and its inhibition in combination with an AR signaling inhibitor synergistically inhibits CRPC cell proliferation and tumor growth [5].

In osteogenesis, Padi2 deficiency in mice leads to a loss of bone mass and a CCD phenotype due to impaired osteoblast differentiation, as Padi2 stabilizes RUNX2 by citrullination, protecting it from ubiquitin-proteasomal degradation [6].

In summary, Padi2 is essential in various biological processes, and its dysregulation is associated with multiple diseases. Studies using gene knockout mouse models have revealed its role in tumor progression, immune-related diseases, and bone formation. These findings provide potential therapeutic targets for treating urothelial cancer, sepsis-induced acute lung injury, endometrial cancer, prostate cancer, and bone diseases.