ACE2 Activation in Intestinal Epithelial Cells Prevents Radiation-Induced Intestinal Injury

Treatment with diminazene aceturate (DIZE), a selective ACE2 agonist, prior to lethal radiation blocked intestinal stem cell (ISC) death, enhanced crypt regeneration, preserved epithelial barrier integrity, and reduced intestinal inflammation, thereby promoting mice survival. Notably, the radioprotective effect of DIZE was reversed by ACE2 or MasR antagonists, and other ACE2 agonists exhibited similar radioprotective efficacy. DIZE treatment improved the survival of ISCs both <i>in vitro</i> and <i>in vivo</i> postradiation. Mechanistically, DIZE directly targeted intestinal epithelial cells (IECs), preventing the activation of radiation-induced MAPK (p38/JNK) and NF-κB pathways. This effect was abolished by ACE2 knockdown in a human intestinal epithelial cell line (HIECs) <i>in vitro</i>. Intriguingly, DIZE failed to inhibit endothelial cell apoptosis or attenuate MAPK/NF-κB pathway activation in irradiated endothelial cells. Preliminary evidence indicates DIZE did not affect the radiosensitivity of colorectal tumor cells or azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumors in mice.Conclusion and Innovation:This study is the first to demonstrate selective ACE2-mediated intestinal protection without compromising tumor radiosensitivity. These findings demonstrate ACE2 activation selectively shields IECs from radiation damage by inhibiting MAPK/NF-κB pathways, offering a novel therapeutic strategy to alleviate RIII without compromising tumor radiosensitivity. <i>Antioxid. Redox Signal.</i> 00, 000-000.