Association of statin use with attenuated radiation-induced intestinal injury and matrix metalloproteinase-9 modulation: Preclinical and clinical evidence

BACKGROUND AND PURPOSE: Radiation therapy (RT) is central to rectal cancer treatment, yet gastrointestinal (GI) toxicity remains a major challenge. Statins have anti-inflammatory and endothelial-protective effects that may offer radioprotection. Preclinical work suggests benefit against radiation-induced intestinal injury, but clinical evidence and mechanistic clarity are limited. We performed a retrospective analysis of patients with rectal cancer receiving neoadjuvant chemoradiation therapy, comparing statin users during RT with matched controls. MATERIALS AND METHODS: GI toxicity was evaluated clinically, and formalin-fixed tissues underwent transcriptomic and histological assessment. Mechanistic findings were tested in a murine abdominal irradiation model was treated with or without the matrix metalloproteinase-9 (MMP-9) inhibitor SB-3CT. Epithelial integrity, inflammation, and bacterial translocation were examined. RESULTS: Grade ≥ 2 GI toxicity were less common among statin users than controls (30.7 % vs. 45.6 %), although the difference was not significant. Statin exposure was associated with lower histological injury scores, preserved crypt structure, and improved epithelial proliferation. Transcriptomic analysis identified 1818 differentially expressed genes, highlighting pathways involved in leukocyte transendothelial migration and tight junction regulation. Statin-treated tissues showed reduced MMP-9 expression and diminished inflammatory infiltration. In mice, MMP-9 inhibition reproduced these protective effects, improving histological architecture, strengthening barrier-related proteins, and lowering inflammatory cytokine levels. CONCLUSIONS: Statins may mitigate radiation-induced intestinal injury by suppressing MMP-9, limiting inflammation, and preserving epithelial barrier function. While the clinical toxicity reduction did not reach significance, convergent histological, molecular, and experimental data identify MMP-9 as a central mediator and support further investigation of statins as adjuncts in pelvic RT.