Lycium barbarum Ameliorates Oral Mucositis via HIF and TNF Pathways: A Network Pharmacology Approach
Authors: Chen Xun , Wu Yanhui , Li Jing , Jiang Sijing , Sun Qiang , Xiao Li , Jiang Xiliang , Xiao Xun , Li Xianxian , Mu Yandong 
Published: July 2024

Background:
Oral mucositis is the most common and troublesome complication for cancer patients
receiving radiotherapy or chemotherapy. Recent research has shown that Lycium barbarum, an important economic
crop widely grown in China, has epithelial protective effects in several other organs. However, it is unknown
whether or not Lycium barbarum can exert a beneficial effect on oral mucositis. Network pharmacology
has been suggested to be applied in “multi-component-multi-target” functional food studies. The purpose
of this study is to evaluate the effect of Lycium barbarum on oral mucositis through network pharmacology,
molecular docking and experimental validation.

Aims:
To explore the biological effects and molecular mechanisms of Lycium barbarum in the treatment of oral
mucositis through network pharmacology and molecular docking combined with experimental validation.

Methods:
Based on network pharmacology methods, we collected the active components and related targets of
Lycium barbarum from public databases, as well as the targets related to oral mucositis. We mapped protein-
protein interaction (PPI) networks, performed gene ontology (GO) and Kyoto Encyclopedia of Genes and
Genomes (KEGG) functional enrichment, and constructed a 'components-disease-targets' network and 'components-
pathways-targets' network using Cytoscape to further analyse the intrinsic molecular mechanisms of Lycium
barbarum against oral mucositis. The affinity and stability predictions were performed using molecular
docking strategies, and experiments were conducted to demonstrate the biological effects and possible mechanisms
of Lycium barbarum against oral mucositis.

Results:
A network was established between 49 components and 61 OM targets. The main active compounds
were quercetin, beta-carotene, palmatine, and cyanin. The predicted core targets were IL-6, RELA, TP53,
TNF, IL10, CTNNB1, AKT1, CDKN1A, HIF1A and MYC. The enrichment analysis predicted that the therapeutic
effect was mainly through the regulation of inflammation, apoptosis, and hypoxia response with the involvement
of TNF and HIF pathways. Molecular docking results showed that key components bind well to the
core targets. In both chemically and radiation-induced OM models, Lycium barbarum significantly promoted
healing and reduced inflammation. The experimental verification showed Lycium barbarum targeted the key
genes (IL-6, RELA, TP53, TNF, IL10, CTNNB1, AKT1, CDKN1A, HIF1A, and MYC) through regulating
the HIF and TNF signaling pathways, which were validated using the RT-qPCR, immunofluorescence staining
and western blotting assays.

Conclusion:
In conclusion, the present study systematically demonstrated the possible therapeutic effects and
mechanisms of Lycium barbarum on oral mucositis through network pharmacology analysis and experimental
validation. The results showed that Lycium barbarum could promote healing and reduce the inflammatory response
through TNF and HIF signaling pathways.