放射線誘導的腸道損傷（Radiation-induced intestinal injury, RIII）是由於骨盆、腹部和腹膜後腫瘤進行放射療法引起的常見消化系統併發症，嚴重影響患者的生活質量，可能導致放射療法的終止。目前，RIII的發病機制尚未完全理解。在此，我們證明了鐵死亡（ferroptosis）在RIII發生中起著關鍵作用。RNA测序分析強烈暗示ferroptosis參與了RIII小鼠的發生。與此相符，RIII小鼠中脂質過氧化的標誌物4-羥基己烯醛（4-hydroxynonenal，4-HNE）和丙二醛（malondialdehyde，MDA）水平顯著增加。並且，ferroptosis抑制劑Ferrostatin-1（Fer-1）改善了小鼠的存活率，減輕了體內腸道纖維化。此外，我們的結果表明，油酸（arachidonic acid，AA）在培養的腸上皮細胞（intestinal epithelial cells，IECs）和體外器官樣結構在放射後增強了ferroptosis，而AA灌注則加重了RIII小鼠中的病情。機制研究顯示，在小鼠空腸和IECs中，放射後，脂肪酸合成酶長鏈家族成員4蛋白（acyl-CoA synthetase long-chain family member 4，ACSL4）水平顯著增加。放射線誘導的IECs ferroptosis在ACSL4敲除或ACSL4功能抑制劑的情況下被阻止。此外，我們發現放射線誘導的ACSL4轉錄受到STAT1/IRF1軸的調控，而AA觸發的AMPK活化則負向調節放射線誘導的ferroptosis。綜上所述，我們的結果表明，ferroptosis介導了RIII的發生，減少膳食中的AA攝入以及靶向STAT1-IRF1-ACSL4軸或AMPK可能是減輕RIII的潛在方法。版權所有 © 2023 作者。由Elsevier B.V.出版。保留所有權利。

Radiation-induced intestinal injury (RIII), a common gastrointestinal complication caused by radiotherapy on pelvic, abdominal and retroperitoneal tumors, seriously affects the life quality of patients and may result in termination of radiotherapy. At present, the pathogenesis of RIII has not been fully understood. Herein, we demonstrated that ferroptosis played a critical role in RIII occurrence. The RNA sequencing analysis strongly hinted ferroptosis was involved in RIII mice. In line with this, the levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), markers of lipid peroxidation, remarkably increased in RIII mice. And the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), improved the mice survival and alleviated intestinal fibrosis in vivo. Moreover, our results revealed that arachidonic acid (AA) enhanced ferroptosis in cultured intestinal epithelial cells (IECs) and organoids in vitro after irradiation, and AA gavage aggravated RIII in mice. Mechanistic studies revealed the level of ACSL4 protein significantly increased in mouse jejunums and IECs after irradiation. Radiation-induced ferroptosis in IECs was also prevented following ACSL4 knockdown or with the function inhibitor of ACSL4. Furthermore, we found that transcription of ACSL4 induced by irradiation was regulated by STAT1/IRF1 axis, and AMPK activation triggered by AA negatively regulated radiation-induced ferroptosis. Taken together, our results suggest that ferroptosis mediates RIII and reducing dietary AA intake as well as targeting the STAT1-IRF1-ACSL4 axis or AMPK may be the potential approaches to alleviate RIII.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.