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Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection

Acta Pharmacologica Sinica volume 44, pages 2253–2264 (2023)Cite this article

Abstract

Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1. In VSV-infected mice, pretreatment with capsaicin improved the survival rate and suppressed inflammatory responses accompanied by attenuated VSV replication in the liver, lung, and spleen. The inhibition of viral replication by capsaicin was independent of TRPV1 and occurred mainly at postviral entry steps. We further revealed that capsaicin directly bound to STAT3 protein and selectively promoted its lysosomal degradation. As a result, the negative regulation of STAT3 on the type I IFN response was attenuated, and host resistance to viral infection was enhanced. Our results suggest that capsaicin is a promising small-molecule drug candidate, and offer a feasible pharmacological strategy for strengthening host resistance to viral infection.

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Fig. 1: Capsaicin restricts viral replication in vitro.
Fig. 2: Capsaicin inhibits virus infection in vivo.
Fig. 3: Capsaicin restricts viral replication after viral entry in a TRPV1-independent manner.
Fig. 4: Capsaicin enhances the antiviral immune response.
Fig. 5: STAT3 negatively regulates the antiviral immune response.
Fig. 6: Capsaicin restricts viral replication by inhibiting STAT3.
Fig. 7: Capsaicin inhibits STAT3 via the autophagy-lysosome pathway.
Fig. 8: Mechanism of capsaicin regulating antiviral immunity pathway.

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Acknowledgements

This work was supported by the Fundamental Research Funds for the Central Universities (No. 2023-JYB-KYPT-06), Young Elite Scientists Sponsorship Program by China Association for Science and Technology (No. 2020-QNRC1-03), the National Natural Science Foundation (NNSF) of China (Nos. 82001663).

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  1. These authors contributed equally: Mei-qi Zhang, Xin Jia

Authors and Affiliations

  1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Mei-qi Zhang, Xin Jia, Ling-dong Kong, Qi-qi Li, Yan-li Yu, Yu-ting He, Qiu-tong Dong & Zhan-hong Jia

  2. School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China

    Cui-qin Cheng, Yu-xi Wang, Yi-ying Li, Fang Xie, Yao Wang & An-long Xu

  3. National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for Metabolic Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China

    Yao Wang & An-long Xu

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Contributions

ALX and YW conceived the study. YW and XJ designed the research, instructed experiments, and helped to revise the manuscript. MQZ performed most of the experiments, analyzed results and wrote the manuscript. CQC and YXW contributed to bioinformatic analysis. QQL, YLY, and YTH instructed article figure drawing. ZHJ, LDK, YYL, QTD, and FX assisted in the design and performance of animal experiment. ALX provided funding for the project, and supervised the project and revised and finally approved the manuscript.

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Correspondence to Yao Wang or An-long Xu.

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Zhang, Mq., Jia, X., Cheng, Cq. et al. Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection. Acta Pharmacol Sin 44, 2253–2264 (2023). https://doi.org/10.1038/s41401-023-01111-9

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