Drug Repurposing of Verapamil for Radiation-Induced Enteropathy: Regulation of 5-LOX, Nrf2, and Intestinal Barrier Function

Abstract

Aim: Radiation-induced intestinal injury is one of the major dose-limiting complications of abdominal radiotherapy and is closely associated with oxidative stress, inflammation, and disruption of epithelial barrier integrity. The present study aimed to investigate the protective effects of verapamil on radiation-induced small-intestinal injury in rats by evaluating histopathological alterations together with tissue levels of TNF-α, 5-LOX, Nrf2, and ZO-1 as markers related to inflammatory, redox-associated, and tight-junction-associated responses. Materials and Methods: Thirty female Wistar albino rats were divided into three groups: Normal Control (n = 10), Radiation + Saline (RAD, n = 10), and Radiation + Verapamil (n = 10). Whole-abdomen irradiation was performed using a single 12 Gy dose delivered by a 6 MV linear accelerator. Verapamil (10 mg/kg/day, s.c.) treatment was started 5 days before irradiation and continued for 5 days afterward. Histopathological injury in jejunal tissues was evaluated using hematoxylin–eosin staining. Tissue levels of TNF-α, 5-LOX, Nrf2, and ZO-1 were measured using ELISA. Results: Whole-abdomen irradiation caused marked histopathological injury characterized by villus disruption, glandular degeneration, and mucosal architectural damage. Irradiation significantly increased small-intestinal TNF-α and 5-LOX levels while decreasing Nrf2 and ZO-1 levels compared with the Normal Control group (p < 0.05). Verapamil treatment significantly attenuated radiation-induced histopathological injury and reduced TNF-α and 5-LOX levels. TNF-α returned to values comparable with the Normal Control group, whereas 5-LOX remained significantly elevated. Verapamil also partially restored Nrf2 and ZO-1 levels compared with the RAD group (p < 0.05), although both remained significantly lower than control levels. Conclusions: Verapamil attenuated radiation-induced small-intestinal injury and was associated with favorable modulation of TNF-α, 5-LOX, Nrf2, and ZO-1 levels. The protective response was partial, with persistent differences in 5-LOX, Nrf2, and ZO-1 compared with controls. These biomarker changes should not be interpreted as direct evidence of functional pathway activation or preservation of intestinal barrier function. Further studies incorporating direct mechanistic and functional assessments are warranted before clinical translation.