Transcription factor PITX2 protects intestinal epithelial cells against inflammatory stress: Implications for ulcerative colitis rectal predilection and therapeutic resistance

Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) primarily characterized by inflammation of the colonic mucosa. Although the disease frequently demonstrates a predilection for the rectum, the underlying mechanism for this specific localization and the reasons for the therapeutic resistance observed in the rectum remain unknown. This study hypothesized that differences in intestinal epithelial cells (IECs) between the lesional rectum and the non-lesional ascending colon contribute to UC pathogenesis. We analyzed gene expression in patient-matched colon organoids to control for individual variables. We identified the transcription factor PITX2 as being elevated in organoids derived from non-lesional ascending colon tissue. Under inflammatory stimulation, PITX2 knockdown significantly reduced the proliferative and sphere-formation capacity of IECs, driven by a marked increase in apoptosis. This heightened vulnerability was independent of enhanced inflammatory signaling (NF-κB) or reactive oxygen species (ROS) production. In conclusion, PITX2 exerts a protective function by promoting IEC survival and inhibiting apoptosis under inflammatory stress. Its relative absence in the rectum may explain why this segment is the primary site of UC onset and therapeutic resistance. PITX2 is a novel candidate molecule regulating the colonic epithelial defense response in IBD.