TNFα signaling in radiation-induced chronic bowel dysfunction suggests therapeutic potential for IBD biologics.

BACKGROUND: Pelvic radiation disease (PRD) arises from normal tissue damage following pelvic radiotherapy and often manifests as bowel dysfunction. Chronic low-grade inflammation is observed in the irradiated mucosa, but its clinical significance remains unclear, as broad-spectrum anti-inflammatory agents show limited efficacy for PRD-related symptoms. However, the potential of targeted biologics used in inflammatory bowel disease (IBD) has not been evaluated, and the chronic inflammatory profile of irradiated mucosa remains undefined. This study sought to evaluate the potential therapeutic utility of IBD biologics by characterizing chronic features of radiation-induced mucosal pathophysiology, with emphasis on low-grade inflammation. METHODS: We performed mRNA sequencing and quantitative mass spectrometry on colorectal mucosal biopsies from pelvic cancer survivors (n = 27), collected 3–20 years post-radiotherapy, and from non-irradiated controls (n = 4). Gene and protein expression were compared across regions with high, low, or no prior radiation exposure. mRNA datasets from Crohn’s disease (n = 127), ulcerative colitis (n = 74), and healthy controls (n = 50) were used for comparative analysis and to identify shared treatment targets. Key findings were validated using complementary techniques and correlated with patient-reported symptoms. RESULTS: Principal Component Analysis (PCA) confirmed dataset comparability and validated low-dose biopsies from PRD patients as suitable internal controls. In mucosa previously exposed to high-dose radiation, central metabolic programs such as heme metabolism, fatty acid metabolism, oxidative phosphorylation, and glycolysis were permanently suppressed, whereas inflammatory and repair pathways were enriched, including angiogenesis, epithelial–mesenchymal transition, DNA repair, cell proliferation, and TNF-α signaling via NF-κB, an important therapeutic target in IBD. Notably, enteroendocrine cells emerged as a source of TNF-α signaling in PRD. Increased IL-8 expression was also observed in PRD mucosa, along with elevated leukocyte-trafficking molecules targeted by anti-integrin therapies. In contrast, there was no or minimal evidence for JAK-STAT signaling, which is downstream of multiple cytokines implicated in IBD-associated inflammation. Individuals with severe bowel symptoms exhibited elevated expression of antigen presentation genes, suggesting a link between persisting immune activation and clinical manifestations. CONCLUSIONS: Years after pelvic radiotherapy, the colorectal mucosa displays a TNF-α–dominated inflammatory–regenerative signature and widespread metabolic suppression. Our findings support further exploration of IBD biologics, particularly TNF-α inhibitors and integrin inhibitors, as potential therapeutic candidates in PRD. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-026-01441-4.