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Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent
Huiyu Zhu1, Yifei Guan2, Wei Wang3
1Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China.
Abstract:
Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.
Insights
Reniformin A (RA) triggers pyroptosis, a cell death pathway, to inhibit non-small-cell lung cancer (NSCLC) growth. This natural compound activates the TLR4/NLRP3/caspase-1/GSDMD pathway, offering a potential NSCLC treatment strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Pyroptosis, an inflammatory programmed cell death, influences tumor progression.
- Reniformin A (RA), from Isodon excisoides, is used in folk medicine for esophageal cancer, but its anti-cancer mechanisms are unknown.
Purpose of the Study:
- To investigate the anti-cancer effects and molecular mechanisms of Reniformin A (RA) in non-small-cell lung cancer (NSCLC).
- To determine if RA can induce pyroptosis and its role in NSCLC treatment.
Main Methods:
- In vitro studies using A549 cells to assess RA's effect on pyroptosis and the TLR4/NLRP3/caspase-1/GSDMD pathway.
- Molecular docking to predict RA's binding to TLR4.
- In vivo experiments in mice to evaluate RA's anti-tumor efficacy and mechanism.
Main Results:
- RA treatment significantly inhibited NSCLC tumor growth in vitro and in vivo.
- RA induced pyroptosis by activating the TLR4/NLRP3/caspase-1/GSDMD axis.
- RA enhanced TLR4 stability and directly bound to TLR4, which was essential for RA-induced pyroptosis.
Conclusions:
- Reniformin A exhibits significant anti-cancer effects in NSCLC by inducing TLR4-mediated pyroptosis.
- RA's mechanism involves the TLR4/NLRP3/caspase-1/GSDMD pathway, suggesting its potential as a novel therapeutic strategy for NSCLC.
