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Published on: March 3, 2023
Qingfei Jiedu decoction inhibits PD-L1 expression in lung adenocarcinoma based on network pharmacology analysis,
Junjie Pan1,2, Hongkuan Yang3, Lihong Zhu1,2
1Department of Pulmonary and Critical Care Medicine, Hangzhou Hospital of Traditional Chinese Medicine (Dingqiao District), Hangzhou, Zhejiang, China.
Abstract:
Objective: We aim at investigating the molecular mechanisms through which the Qingfei Jiedu decoction (QFJDD) regulates PD-L1 expression in lung adenocarcinoma (LUAD). Methods: Bioactive compounds and targets of QFJDD were screened from TCMSP, BATMAN-TCM, and literature. Then, GeneCard, OMIM, PharmGKB, Therapeutic Target, and DrugBank databases were used to identify LUAD-related genes. The protein-protein interaction (PPI) network was constructed using overlapping targets of bioactive compounds in LUAD with the Cytoscape software and STRING database. The potential functions and pathways in which the hub genes were enriched by GO, KEGG, and DAVID pathway analyses. Molecular docking of bioactive compounds and key genes was executed via AutoDock Vina. Qualitative and quantitative analyses of QFJDD were performed using UPLC-Q-TOF-MS and UPLC. Expressions of key genes were determined by qRT-PCR, immunoreactivity score (IRS) of PD-L1 was assessed by immunohistochemistry (IHC), while the CD8+PD-1+T% derived from spleen tissues of Lewis lung cancer (LLC) bearing-mice was calculated using flow cytometry (FCM). Results: A total of 53 bioactive compounds and 288 targets of QFJDD as well as 8151 LUAD associated genes were obtained. Further, six bioactive compounds, including quercetin, luteolin, kaempferol, wogonin, baicalein, and acacetin, and 22 hub genes were identified. The GO analysis showed that the hub genes were mainly enriched in DNA or RNA transcription. KEGG and DAVID pathway analyses revealed that 20 hub genes were primarily enriched in virus, cancer, immune, endocrine, and cardiovascular pathways. The EGFR, JUN, RELA, HIF1A, NFKBIA, AKT1, MAPK1, and MAPK14 hub genes were identified as key genes in PD-L1 expression and PD-1 checkpoint pathway. Moreover, ideal affinity and regions were identified between core compounds and key genes. Notably, QFJDD downregulated EGFR, JUN, RELA, HIF1A, NFKBIA, and CD274 expressions (p < 0.05), while it upregulated AKT1 and MAPK1 (p < 0.05) levels in A549 cells. The PD-L1 IRS of LLC tissue in the QFJDD high dose (Hd) group was lower than model group (p < 0.01). CD8+PD-1+T% was higher in the QFJDD Hd group than in normal and model groups (p < 0.05). Conclusion: QFJDD downregulates PD-L1 expression and increases CD8+PD-1+T% via regulating HIF-1, EGFR, JUN and NFκB signaling pathways. Therefore, QFJDD is a potential treatment option for LUAD.
Insights
Qingfei Jiedu decoction (QFJDD) shows potential for treating lung adenocarcinoma (LUAD) by downregulating PD-L1 expression and enhancing anti-tumor immunity. This traditional Chinese medicine regulates key signaling pathways, offering a novel therapeutic avenue.
Area of Science:
- Integrative oncology and traditional Chinese medicine research.
- Molecular mechanisms of cancer immunotherapy.
Background:
- Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality.
- Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint target in cancer therapy.
- Qingfei Jiedu decoction (QFJDD) is a traditional Chinese medicine with potential anti-cancer properties.
Purpose of the Study:
- To elucidate the molecular mechanisms by which QFJDD regulates PD-L1 expression in LUAD.
- To identify key targets and pathways modulated by QFJDD in LUAD treatment.
Main Methods:
- Bioinformatic analysis of QFJDD compounds and targets against LUAD-related genes.
- Construction of protein-protein interaction networks and pathway enrichment analysis (GO, KEGG).
- Molecular docking, UPLC-Q-TOF-MS, qRT-PCR, immunohistochemistry (IHC), and flow cytometry (FCM) in vitro and in vivo.
Main Results:
- Identified six core bioactive compounds and 22 hub genes, with enrichment in transcription, cancer, and immune pathways.
- Key genes (EGFR, JUN, RELA, HIF1A, NFKBIA) involved in PD-L1 regulation were identified.
- QFJDD downregulated key oncogenic gene expressions, reduced PD-L1 levels, and increased CD8+PD-1+T cells in a Lewis lung cancer model.
Conclusions:
- QFJDD effectively downregulates PD-L1 expression and enhances anti-tumor T-cell activity in LUAD.
- The mechanism involves the regulation of HIF-1, EGFR, JUN, and NFκB signaling pathways.
- QFJDD represents a promising therapeutic candidate for LUAD treatment.
