Circadian Regulator PER2 Protects Against Epithelial Necroptosis in Ulcerative Colitis via the STAT1–ZBP1 Axis

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by epithelial barrier disruption, excessive cell death, and dysregulated immune signaling. While circadian rhythms are known to influence immune homeostasis, the role of the core circadian regulator Period circadian clock 2 (PER2) in intestinal inflammation remains poorly understood. Methods: We investigated the impact of circadian rhythm disruption on colitis severity using a jet lag model in DSS-treated mice, as well as clinical UC samples from patients with or without sleep disorders. Epithelial-specific Per2 knockout ( Per2 ^-/- ) mice and in vitro PER2 knockdown models were employed to dissect the mechanistic role of PER2 in regulating epithelial cell death and inflammation. Bulk RNA-sequencing, molecular docking, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were used to identify downstream targets and interacting partners. Pharmacological inhibition of STAT1 using Nifuroxazide was tested for therapeutic potential. Results: Circadian disruption aggravated DSS-induced colitis in mice and increased epithelial apoptosis in UC patients, accompanied by marked suppression of PER2 expression. Loss of PER2 in mice resulted in exacerbated intestinal inflammation, elevated DAI scores, and histological damage. Transcriptomic profiling and functional assays revealed that PER2 deficiency promoted necroptosis by upregulating ZBP1, RIPK3, and MLKL at both transcriptional and protein levels. Mechanistically, PER2 directly interacts with STAT1 via its PAS1 domain and restrains STAT1-mediated transcription of Zbp1. Inhibition of STAT1 by Nifuroxazide ameliorated colitis severity and suppressed necroptotic signaling in Per2 ^-/- mice, highlighting the PER2–STAT1–ZBP1 axis as a key pathway linking circadian disruption to epithelial injury. Conclusion: Our findings identify PER2 as a critical suppressor of intestinal epithelial necroptosis and inflammation, acting through inhibition of STAT1-dependent ZBP1 activation. Circadian rhythm disruption impairs this protective pathway, exacerbating colitis severity. Pharmacological targeting of STAT1 may offer a novel therapeutic strategy for UC patients with circadian rhythm dysregulation.