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Activating NK cell immunity against prostate cancer with Hedysarum polybotrys Hand.-Mazz.: A multi-omics integration
Lianghui Zhan1, Qian Liu2, Changjun Zhang3
1Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310014, China; Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310014, China; Zhejiang Key Discipline in Traditional Chinese Medicine for Pharmaceutical Botony, Hangzhou, Zhejiang, 310014, China; Zhejiang Engineering Research Center for Quality Assessment and Development of Dao-di Herbs, Hangzhou, Zhejiang, 310014, China.
Ethnopharmacological Relevance:
Hedysarum polybotrys Hand.-Mazz. (Hongqi, HQ) is a prized Qi-tonifying herb in Traditional Chinese Medicine (TCM), historically employed to enhance the body's resistance and modulate immune function. While its anti-tumor properties are recognized, the specific immunomodulatory mechanisms by which HQ empowers Natural Killer (NK) cells to combat prostate cancer (PCa) remain under-explored.
Aim Of The Study:
To systematically elucidate the material basis and molecular mechanisms through which the aqueous extract of HQ enhances NK cell-mediated cytotoxicity against PCa cells, utilizing an integrated approach of multi-omics and experimental validation.
Methods:
The chemical profile of HQ aqueous extract was characterized using UHPLC-MS/MS untargeted metabolomics. Network pharmacology and transcriptomic analyses (RNA-seq) were integrated to predict core targets and signaling pathways. Specific interactions were simulated via molecular docking. Validations were performed using an in vitro co-culture model of NK-92 and PC-3 cells. Assays included CCK-8, LDH release, flow cytometry (apoptosis, surface markers), ELISA (cytokines), and Western blot.
Results:
A total of 69 compounds were identified in HQ, with Genistein and Isoliquiritigenin highlighted as key active constituents. HQ treatment significantly enhanced NK-92 cell cytotoxicity against PC-3 cells, evidenced by increased LDH release and PC-3 apoptosis. Mechanistically, HQ upregulated the expression of cytolytic effectors (Perforin, Granzyme B) and pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17A). Crucially, HQ treatment achieved a "dual-effect": it reactivated the PI3K/AKT signaling pathway in NK cells (confirmed by increased p-PI3K and p-AKT levels) while concurrently downregulating the immunosuppressive PD-1/PD-L1 checkpoint axis.
Conclusion:
This study demonstrates that HQ potentiates NK cell anti-tumor immunity against prostate cancer through a dual mechanism involving PI3K/AKT pathway activation and PD-1/PD-L1 axis inhibition. These findings provide modern pharmacological evidence supporting the traditional use of HQ for enhancing immune surveillance in cancer therapy.
