Radiation enteritis (RE) is a common side effect of radiotherapy, with no specific therapeutic agents available. Sophora alopecuroides L. (KDZ) has been used in China for many years to treat gastrointestinal disorders, and matrine, oxymatrine, and aloperine (ALO) are its main alkaloid components. We found that ALO significantly attenuated the damage of ionizing radiation (IR) to the viability of intestinal epithelial cells (IECs), outperforming matrine and oxymatrine. The IR-induced Fe²⁺ accumulation, lipid peroxidation and down-regulated glutathione peroxidase 4 and solute carrier family 7 member 11 levels were restored, and ferroptosis but not apoptosis or necrosis was further indicated. Untargeted metabolomic analysis showed that ALO shifted the glucose flux from glycolysis to the hexosamine biosynthetic pathway to elevate the UDP-GlcNAc level. Notably, ALO could directly bind with taste 2 receptor member 138 (TAS2R138) as one of its potential targets, and promoted the activation of downstream signaling molecules phospholipase C β (PLCβ) and α-gustducin. Furthermore, ALO enhanced the association of PLCβ and GAPDH at MET56 and LYS271, and inhibiting the latter’s acetylation and activity via activating TAS2R138. In addition, after triggering the metabolic reprogramming, ALO promoted the O/N-glycosylation to prevent the lysosomal degradation of ferritin heavy chain 1 and transferrin receptor, modulating iron storage and transport, thus alleviating ferroptosis. In vivo, the above-mentioned effect and mechanisms of ALO were demonstrated using the model of RE in mice. Collectively, ALO activated TAS2R138 to promote the interaction of PLCβ and GAPDH to induce metabolic reprogramming and alleviate IR-induced ferroptosis of IECs to improve RE.