Jing-Nan Zhang,1,* Ke-Di Li,1,* Zhang-Jing Cao,1 Li-Yue Xu,1 Xiao-Lan Zhao,1 Fei Tang,1 Fu Peng,2 Cheng Peng,1 Hui Ao1 

1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hui Ao, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China, Email aohui2005@126.com Cheng Peng, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China, Email pengchengcxy@126.com

Purpose: Chemotherapy-induced mucositis (CIM) causes severe gastrointestinal symptoms in cancer patients. Magnoliae Officinalis Cortex, a traditional medicine, has demonstrated therapeutic promise in mitigating intestinal mucositis and gastrointestinal disorders, with advantages including marked efficacy and low adverse effect profiles compared to conventional pharmacotherapies. However, the therapeutic potential and mechanisms of the volatile oil of Magnoliae Officinalis Cortex (MagO) against CIM remain elusive. This study aimed to investigate the protective effects and mechanisms of MagO against 5-Fluorouracil (5-FU)-induced mucositis in mice via integrated multi-omics approaches.
Methods: CIM model was established in ICR mice via intraperitoneal injection of 5-FU. The therapeutic effect of MagO on 5-FU-induced CIM was evaluated by monitoring body weight, diarrhea score, spleen index, ileum histopathology, and measuring DAO, D-LA, and inflammatory cytokines levels in serum. Metabolites and gut microbiota were analyzed through non-targeted metabolomics and 16S rDNA sequencing. Furthermore, potential mechanisms of MagO were assessed via GC-MS, network pharmacology, molecular docking, Western blot, and RT-qPCR.
Results: MagO ameliorated 5-FU-induced intestinal mucosal injury and barrier dysfunction, as evidenced by significantly increased body weight rate reduced diarrhea scores, and alleviated ileum tissue damage. It also decreased IL-1β, IL-6, TNF-α, D-LA, and DAO levels in serum. Furthermore, MagO restored gut microbiota composition and metabolite profiles, specifically modulated the arachidonic acid metabolism by promoting PGE2 synthesis and upregulating EP2 and EP4 expressions. Mechanistic studies demonstrated that MagO exerted anti-CIM effects through inhibition of the PI3K/AKT signaling pathway, upregulation of Bcl-2 and intestinal barrier proteins (ZO-1, Occludin) expressions, and downregulation of Bax expression.
Conclusion: MagO mitigated CIM by modulating the PI3K/AKT signaling pathway and the PGE2/EP2/EP4 axis, restoring gut microbiota and metabolites composition, reducing apoptosis, and improving intestinal permeability.

Keywords: Magnoliae Officinalis Cortex volatile oil, 5-fluorouracil, CIM, PI3K/AKT signaling pathway, prostaglandin E2