Activation of pyroptosis and ferroptosis is involved in radiation-induced intestinal injury in mice

Abstract

Radiation-induced intestinal injury (RIII) is one of the most common abdominal and pelvic radiation therapy complications. RIII seriously affects the treatment and prognosis of cancer patients, and there are no effective interventions. Radiation can cause intestinal tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release. We established an RIII mouse model by subjecting C57BL/6 mice to abdominal irradiation. Our results show that both pyroptosis and ferroptosis play a key role in RIII. VX-765 and Ferrostatin-1 (Fer-1) can inhibit these two types of programmed cell death and ameliorate RIII, respectively. Activation of the nuclear factor-κB (NF-κB) signaling pathway exacerbates the chemotaxis of inflammatory cells. In the present study, we hypothesized that the activation of NF-κB signaling pathway plays an important role in intestinal inflammatory injury. We demonstrated that the nuclear expression levels of the NF-κB subunit p65 increased after irradiation treatment. Reduced release of inflammatory factors and intestinal tissue damage was observed after pretreatment with pyrrolidinedithiocarbamate ammonium (PDTC). Moreover, after PDTC treatment, the indicators related to pyroptosis and ferroptosis were reversed. Collectively, these results suggest that the activation of the intestinal NF-κB signaling pathway may be associated with pyroptosis, ferroptosis, and subsequent intestinal injury after irradiation.