Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by immune dysregulation, particularly the imbalance between T helper 1 (Th1) and regulatory T (Treg) cells, which plays a crucial role in its pathogenesis. Members of the protein tyrosine phosphatase (PTP) family are involved in immune regulation, and the protein tyrosine phosphatase receptor-type O (PTPRO) is significantly upregulated in inflamed tissues. However, the specific role of PTPRO in UC remains unclear. This study aimed to investigate the role and mechanisms of PTPRO in UC to identify new therapeutic targets.

Methods: A mouse model of UC was induced using dextran sulfate sodium (DSS), and PTPRO expression was examined in the colonic tissues of both mice and UC patients. PTPRO knockout (PTPRO^-/-) mice were used to assess the impact of PTPRO deficiency on UC severity and the regulation of Th1/Treg cell balance. Primary T cells were isolated from mice to explore the signaling pathways regulated by PTPRO.

Results: PTPRO expression was significantly elevated in inflamed colonic tissues from both DSS-treated mice and UC patients (p < 0.05). PTPRO^-/- mice exhibited attenuated colitis, manifesting as reduced body weight loss, lower Disease Activity Index (DAI) scores, and markedly improved histopathology compared to wild-type (WT) mice (all p < 0.05). Knockout of PTPRO reduced colonic levels of pro-inflammatory cytokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)) while increasing anti-inflammatory mediators (interleukin-10 (IL-10) and Forkhead box P3 (Foxp3)) (p < 0.05). Consistently, flow cytometry analysis demonstrated that PTPRO^-/- mice had fewer Th1 cells and more Tregs in the colon, suggesting the restoration of immune homeostasis (p < 0.05). Mechanistically, PTPRO was found to interact with Janus kinase 2 (JAK2) and function as a negative regulator of JAK2–signal transducer and activator of transcription 5 (STAT5) signaling. Loss of PTPRO led to increased phosphorylation of JAK2 and STAT5, thereby promoting Treg differentiation, whereas in vivo JAK2 inhibition reversed these effects.

Conclusion: PTPRO regulates the Th1/Treg balance via the JAK2-STAT5 pathway, and its absence shifts the immune response toward anti-inflammatory Tregs, highlighting PTPRO as a potential therapeutic target for UC.