ZhiXie capsule mitigates ionizing radiation-induced intestinal injury by inhibiting PI3K/AKT signaling pathway

This study aimed to investigate the therapeutic effects of Zhixie Capsule (ZXC) on ionizing radiation (IR)-induced intestinal injury (radiation enteritis, RE) and to elucidate the underlying molecular mechanisms, focusing on the PI3K/AKT signaling pathway. A rat model of RE was established by 12 Gy abdominal IR. ZXC was administered daily for 7 days, and its effects were evaluated by monitoring body weight, disease activity index (DAI), colon length, histopathology (H&E), and intestinal barrier integrity (Alcian blue staining, FITC-dextran permeability assay, and immunofluorescence for ZO-1 and occludin). Network pharmacology was used to predict key pathways. Inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10) were measured by ELISA, and pathway protein expression (p-PI3K, p-AKT, p-IKKβ, p-p65) was analyzed by Western blot. A rescue experiment using the PI3K activator YS49 was performed to confirm pathway specificity. In terms of results, ZXC dose-dependently alleviated RE manifestations, including weight loss, colonic shortening, and histological damage, and improved intestinal barrier integrity, as evidenced by increased goblet cell numbers and upregulated expression of tight junction proteins. Network pharmacology predicted the potential involvement of the PI3K/AKT axis. Mechanistically, ZXC suppressed IR-induced PI3K/AKT phosphorylation and downstream NF-κB activation, reducing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and increasing IL-10 levels. These protective effects were partially reversed by YS49, suggesting that ZXC mitigates RE by inhibiting PI3K/AKT-mediated inflammation and improving mucosal barrier integrity, highlighting its potential as a radiomitigative strategy.