Targeting Kynureninase Attenuates Radiation‐Induced Intestinal Injury via MAPK Signaling Suppression

Kynureninase (KYNU), a key enzyme in the tryptophan-kynurenine metabolic pathway, has been increasingly recognized for its role in immune regulation and inflammation. However, its involvement in radiation-induced intestinal injury (RIII) has not been fully elucidated. In this study, we identified a significant upregulation of KYNU expression in the colonic tissues of mice with RIII using transcriptomic analysis and experimental validation. Functional assays demonstrated that KYNU knockdown in NCM460 human intestinal epithelial cells attenuated radiation-induced apoptosis and oxidative stress, while promoting cell proliferation. Mechanistically, RNA sequencing (RNA-seq) and pathway enrichment analyses revealed that KYNU regulates the mitogen-activated protein kinase (MAPK) signaling pathway, as KYNU silencing reduced the phosphorylation levels of key MAPK proteins (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], and p38) following irradiation. Importantly, pharmacological inhibition of KYNU using carbidopa (CBP) significantly mitigated radiation-induced epithelial injury in vitro. In the RIII mouse model, CBP administration (prevention and treatment) increased the number of crypts, improved intestinal epithelial structure, and maintained the integrity of the intestinal barrier. These findings demonstrate, that KYNU plays a critical role in the pathogenesis of RIII and that its inhibition confers protection against intestinal damage by suppressing MAPK-mediated inflammatory responses. Targeting KYNU may thus offer a promising therapeutic strategy for the prevention and treatment of RIII.