Nutritional Modulation of Melatonin‐SIRT1 Signaling by Octanoic Acid‐Rich Enteral Nutrition Protects Against Radiation‐Induced Intestinal Injury

Radiation-induced intestinal injury (RIII) is a common complication in patients under radiotherapy for abdominopelvic and retroperitoneal malignancies, significantly impairing quality of life and overall survival. However, the therapeutic effect of standard enteral nutrition (EN) is limited. This study aimed to investigate the protective role and potential mechanisms of octanoic acid (OA)-rich EN in RIII. C3H/HeN mice were randomly assigned to four groups: Sham, Radiation (RI), RI + EN and RI + OA-rich EN to investigate the impacts of OA-rich EN. Then mice were randomly assigned to five groups: Sham, RI, RI + OA-rich EN, RI + OA-rich EN + Luzindole, RI + OA-rich EN + EX527 to examine whether OA-rich EN alleviated RIII through the melatonin-silent information regulator 1 (SIRT1) pathway. We evaluated the intestinal histopathology, apoptosis, tight junction protein expression and permeability. Moreover, melatonin and inflammatory cytokine levels were measured in the intestine and serum. SIRT1/Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α)/Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) pathway was also assessed. OA-rich EN promoted melatonin secretion in the intestine and serum, activated the SIRT1/PGC-1α/PPARγ pathway, markedly improved intestinal histopathology, and significantly reduced levels of inflammatory factors in intestine and serum. These beneficial effects were greater than EN alone. Furthermore, these beneficial effects were abolished when OA-rich EN was co-administered with either a melatonin antagonist or a SIRT1 inhibitor. This is the first confirmation that OA-rich EN alleviated RIII by promoting melatonin secretion, which in turn activated the SIRT1/PGC-1α/PPARγ pathway. Our findings highlight OA-rich EN as a promising nutritional strategy to improve intestinal health and reduce treatment-related complications in patients receiving abdominal radiotherapy.