WTAP-mediated m6A modification of PTPN1 contributes to ulcerative colitis pathogenesis through regulating colonic epithelial cell phenotypes.

Relapsing and remitting mucosal inflammation can potentially spread throughout the colon in cases of ulcerative colitis (UC). N6-methyladenosine (m6A) is the most prevalent epigenetic change in RNA, and it is essential to numerous biological processes and diseases, including UC. This study aims to investigate the roles and mechanisms of Wilms tumor 1-associated protein (WTAP) and protein tyrosine phosphatase non-receptor type 1 (PTPN1) in the etiology of UC and as potential therapeutic targets. PTP1B (gene name PTPN1) was significantly upregulated in UC samples and lipopolysaccharide (LPS)-stimulated NCM460 cells, influencing cell viability, DNA synthesis, and apoptosis. WTAP was identified as an upregulated methyltransferase in UC and was found to enhance PTPN1 expression through m6A modification, thereby exacerbating LPS-induced inflammation and cellular dysfunction. The use of the m6A modification inhibitor Cycloleucine and PTPN1 knockdown attenuated these effects, highlighting the effect of WTAP-mediated m6A modification of PTPN1 on UC pathophysiology. Our findings indicate the significant role of the WTAP-mediated m6A modification of PTPN1 in exacerbating UC-related inflammation and cellular dysfunction. Targeting the WTAP-PTPN1 axis could provide a novel therapeutic approach for managing UC, thereby addressing the unmet need for effective treatments in patients who are unresponsive to current treatment regimens.