Paeoniflorin protects against radiation enteritis by suppressing YY1/ACSL4 axis to attenuate murine intestinal epithelial injury and ferroptosis.

Abstract

BACKGROUND: Radiation enteritis (RE), an intestinal complication due to abdominal or pelvic radiotherapy, severely impacts patients' life and health. Paeoniflorin (PF), a water-soluble monoterpene glycoside, is reported to relieve RE, but its molecular mechanism needs further exploration. Thus, this study aims to clarify the molecular mechanism underlying PF's effect on RE. METHODS: An in vitro ionizing radiation (IR)-induced cell model was constructed. Subsequently, CCK-8, EdU, flow cytometry and relevant kits were applied to examine cellular behaviors and ferroptosis. Protein and mRNA expression levels were assessed via Western blot and qRT-PCR. Bioinformatics tools, ChIP, and dual-luciferase reporter assays were employed to ascertain the regulatory relationship between YY1 and ACSL4. Furthermore, the RE mouse model was established for in vivo experiments. RESULTS: PF inhibited ionizing radiation (IR)-induced injury and ferroptosis in mouse intestinal epithelial cells (IEC-6). The inhibitory effect of PF was mediated by inhibiting ACSL4. YY1 activated the transcription of ACSL4 to promote its expression. Moreover, ACSL4 upregulation abrogated the protective effect of silencing YY1 on cell damage induced by IR. PF curbed YY1 expression, thereby suppressing the damage to IEC-6 cells induced by IR. Besides, PF constrained ACSL4 and the progression of radiation enteritis in vivo. CONCLUSION: PF alleviated IR-induced damage and ferroptosis of IEC-6 cells by targeting the YY1/ACSL4 axis, providing a novel mechanistic basis for its application in RE treatment.