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Mechanism of zedoary turmeric oil multi-components targeting S100A14 to reprogram astrocytes against tumor brain
Xue-Yu Wang1, Jin-Ru Liu1, Zeng-Yuan Yao1
1International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Background:
Zedoary Turmeric Oil (ZTO) is an active extract derived from the traditional Chinese medicine Ezhu, which is conventionally used to promote blood circulation, remove blood stasis, and relieve pain. Nevertheless, the therapeutic potential and underlying molecular mechanism of ZTO against tumor brain metastasis (BrM) remain poorly elucidated.
Methods:
The anti-BrM efficacy of ZTO was firstly assessed through S100A14-overexpress tuomor cells intracarotid injection BrM mice model. Concurrently, GC-MS analysis, computer simulation, along with in vitro experiments were employed to comprehensively investigate the mechanism by which ZTO targets S100A14 to suppress BrM.
Results:
Our study first identified ZTO as a promising candidate against S100A14-driven BrM. In mouse model, high-dose ZTO (200 mg/kg) significantly reduced in vivo brain BLI from 21465.73 ± 20757.36 to 1417.37 ± 2878.98 in 4T1-S100A14 breast cancer. ZTO also exhibited concentration-dependent BrM inhibition effects in LLC S100A14 lung cancer. ZTO remodeled the BrM microenvironment by regulating GFAP+ astrocytes via the NF-κB pathway, inhibiting migration, invasion, EMT, and MMPs. Additionally, ZTO dose-dependently suppressed the secretion of IL-6, CCL2, and CXCL1, thereby reducing recruitment of both P-MDSCs and M-MDSCs. Multi-analysis revealed that Curdione, Curzerene, Germacrone, Curcumenol, and Curcumenone directly bind S100A14, enhancing its thermal stability and resistance to protease hydrolysis. CETSA results confirmed thermal stabilization: Curzerene ΔTm = +22 °C, Germacrone ΔTm = +14.2 °C, Curdione ΔTm = +17.7 °C.
Conclusion:
ZTO exhibited potent anti-BrM efficacy and the mechanism involved multiple components synergistically targeting S100A14 to reprogram astrocytes, which in turn reduced the secretion of pro-inflammatory factors, thereby inhibiting the recruitment of MDSCs and reshaping the immunosuppressive microenvironment of the brain. Collectively, our study provides the first experimental evidence that the multiple bioactive components in ZTO act synergistically to target S100A14, offering a promising new direction for the development of anti-BrM therapeutic strategies.