Low-dose 5-hydroxymethylfurfural mitigates radiation -induced intestinal toxicity via HIF2α-driven IL22/STAT3 signaling enhancement.

BACKGROUND: Ionizing radiation (IR)-induced intestinal injury limits the efficacy of radiotherapy for abdominal/pelvic malignancies, and there are few effective preventive measures. 5-Hydroxymethylfurfural (5-HMF), a bioactive compound abundant in heat-processed foods and herbal decoctions, has shown therapeutic benefits in inflammatory diseases, yet its role in IR-induced intestinal damage remains unclear. METHODS: C57BL/6 male mice (n = 15~17/group) were administered intraperitoneal vehicle, low-dose (50 mg/kg/day), or high-dose (200 mg/kg/day) 5-HMF for 7 days prior to 8–10 Gy of whole-body irradiation (WBI) or total abdominal irradiation (TAI). Assessments included survival, weight recovery, intestinal permeability, crypt survival, as well as proliferation and apoptosis of intestinal stem cells (ISCs). Mechanistic investigations utilized RNA sequencing of crypts, organoid cultures, dual luciferase assays, and pharmacological hypoxia-inducible factor-2α (HIF-2α) inhibition (PT-2385) to explore the radioprotective mechanisms of 5-HMF. RESULTS: Compared with the control group or high-dose group, low-dose 5-HMF significantly improved survival, accelerated weight recovery, and enhanced crypt regeneration. It promoted ISCs proliferation while inhibiting apoptosis. Mechanistically, 5-HMF stabilized HIF-2α, which bound to hypoxia-response elements (HREs) in the Interleukin-22 receptor-1 (IL22R1) promoter, thereby upregulating IL22R1 expression and amplifying IL22-dependent signal transducer and activator of transcription 3 (STAT3) phosphorylation. Importantly, PT-2385-mediated HIF-2α inhibition abolished the effects of 5-HMF on IL22R1/STAT3 and its radioprotective role both in vivo and in organoids. CONCLUSIONS: Low-dose 5-HMF protects against IR-induced intestinal injury by stabilizing HIF-2α to enhance IL22/STAT3 signaling and drive ISC-mediated epithelial regeneration, identifying it as a promising dietary-derived radioprotectant for such damage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07757-3.