Arachidonic acid enhances ferroptosis leading to occurrence of radiation-induced intestinal injury

China: A recent study for the first time has shown dietary arachidonic acid (AA) promotes the occurrence of radiation-induced intestinal injury (RIII).

The research, published in Redox Biology was led by Prof. HAN Wei from Hefei Institutes of Physical Science (HFIPS), Chinese Academy of Sciences (CAS). 

RIII is a common gastrointestinal complication (incidence rate is about 80%) caused by radiotherapy on pelvic, abdominal, and retroperitoneal tumours. It may lead to the interruption of radiotherapy. At present, no unified and effective methods are available for the clinical treatment of RIII. Therefore, determining the pathogenesis of RIII is an important prerequisite for developing the strategies for RIII treatment.

In this study, the team utilized RNA sequencing analysis to investigate the possible involvement of ferroptosis in RIII mice's intestinal tissue. As a result, the levels of lipid peroxidation markers, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), were significantly elevated in these mice.

The researchers also discovered that Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was successful in mitigating both death and intestinal fibrosis in RIII mice. Furthermore, in cultured intestinal epithelial cells (IECs), organoids and mouse models, researchers found that AA, the omega-6 essential fatty acid, is a key factor in radiation-induced ferroptosis. Exogenous AA triggered radiation-induced ferroptosis.

Subsequent mechanistic studies revealed that the activation of STAT1-IRF1 positively regulated the expression of ACSL4, which promoted the occurrence of ferroptosis after radiation. On the other hand, the AMPK signaling pathway was activated by AA and played a negative regulatory role in radiation-induced ferroptosis.

The above results indicated that the STAT1-IRF1-ACSL4 and AMPK signaling pathways were potential molecular targets for the strategies development of RIII prevention and treatment. Arachidonic acid, an essential dietary fatty acid, was an important risk factor for ferroptosis-mediated RIII. This study also suggested that targeted dietary nutrition control, which was expected to alleviate RIII, should be implemented during radiotherapy.

Reference:

Peizhong Kong, Miaomiao Yang, Ying Wang, K.N. Yu, Lijun Wu, Wei Han, Ferroptosis triggered by STAT1- IRF1-ACSL4 pathway was involved in radiation-induced intestinal injury, Redox Biology, https://doi.org/10.1016/j.redox.2023.102857