Regorafenib As a Potential Drug for Severe COVID-19: Inhibition of Inflammasome Activation in Mice

Overview

Journal FEBS Open Bio

Date 2025 Feb 3

PMID 39895416

Authors

Ju Hwan Jeong

Sun-Ok Kim

Seong Cheol Min

Eung-Gook Kim

Min-Suk Song

Eun-Young Shin

Affiliations

Soon will be listed here.

Abstract

SARS-CoV-2 infection can lead to severe COVID-19, particularly in elderly individuals and those with compromised immunity. Cellular senescence has been implicated as a key pathogenic mechanism. This study investigated the therapeutic potential of regorafenib, a previously characterized senomorphic drug, for severe COVID-19. SARS-CoV-2 virus-infected K18-hACE2 mice, overexpressing the human ACE2 receptor, exhibited 100% mortality by 10 days post infection. Regorafenib treatment significantly improved survival rates, approximately 43% remaining alive. Mechanistically, regorafenib effectively suppressed type I and II interferon and cytokine signaling. Notably, regorafenib inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a key driver of the cytokine storm associated with severe COVID-19. Our findings elucidate the molecular mechanisms underlying therapeutic effects of regorafenib and suggest its potential use as a promising treatment option for severe COVID-19.

References

Tai G, Yu Q, Li J, Wei W, Ji X, Zheng R . NLRP3 inflammasome links vascular senescence to diabetic vascular lesions. Pharmacol Res. 2022; 178:106143. DOI: 10.1016/j.phrs.2022.106143. View

Li X, Ma L, Huang K, Wei Y, Long S, Liu Q . Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway. Int J Mol Sci. 2021; 22(4). PMC: 7922359. DOI: 10.3390/ijms22041985. View

Schroder K, Tschopp J . The inflammasomes. Cell. 2010; 140(6):821-32. DOI: 10.1016/j.cell.2010.01.040. View

Tian R, Zhu Y, Yao J, Meng X, Wang J, Xie H . NLRP3 participates in the regulation of EMT in bleomycin-induced pulmonary fibrosis. Exp Cell Res. 2017; 357(2):328-334. DOI: 10.1016/j.yexcr.2017.05.028. View

Oh K, Lee G, Kim H, Park J, Shin E, Kim E . Regorafenib prevents the development of emphysema in a murine elastase model. BMB Rep. 2023; 56(8):439-444. PMC: 10471461. View

Ettrich T, Seufferlein T . Regorafenib. Recent Results Cancer Res. 2018; 211:45-56. DOI: 10.1007/978-3-319-91442-8_3. View

Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H, Zhao J . Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature. 2022; 606(7914):585-593. PMC: 9288243. DOI: 10.1038/s41586-022-04802-1. View

McGeough M, Wree A, Inzaugarat M, Haimovich A, Johnson C, Pena C . TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. J Clin Invest. 2017; 127(12):4488-4497. PMC: 5707143. DOI: 10.1172/JCI90699. View

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

10.

McCray Jr P, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L . Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol. 2006; 81(2):813-21. PMC: 1797474. DOI: 10.1128/JVI.02012-06. View

11.

Roberts A, Trapnell C, Donaghey J, Rinn J, Pachter L . Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol. 2011; 12(3):R22. PMC: 3129672. DOI: 10.1186/gb-2011-12-3-r22. View

12.

Linden T, Hanses F, Domingo-Fernandez D, DeLong L, Tom Kodamullil A, Schneider J . Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases. Artif Intell Life Sci. 2022; 1:100020. PMC: 8677630. DOI: 10.1016/j.ailsci.2021.100020. View

13.

Zeng J, Xie X, Feng X, Xu L, Han J, Yu D . Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice. EBioMedicine. 2022; 75:103803. PMC: 8719059. DOI: 10.1016/j.ebiom.2021.103803. View

14.

Winkler E, Bailey A, Kafai N, Nair S, McCune B, Yu J . SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020; 21(11):1327-1335. PMC: 7578095. DOI: 10.1038/s41590-020-0778-2. View

15.

Strumberg D, Scheulen M, Schultheis B, Richly H, Frost A, Buchert M . Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012; 106(11):1722-7. PMC: 3364125. DOI: 10.1038/bjc.2012.153. View

16.

Rathinam V, Zhao Y, Shao F . Innate immunity to intracellular LPS. Nat Immunol. 2019; 20(5):527-533. PMC: 7668400. DOI: 10.1038/s41590-019-0368-3. View

17.

Zhang Z, Zhang H, Zhang Y, Zhang Q, Liu Q, Hu Y . Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase. Virol Sin. 2023; 38(3):470-479. PMC: 10148713. DOI: 10.1016/j.virs.2023.04.008. View

18.

Weisberg E, Parent A, Yang P, Sattler M, Liu Q, Liu Q . Repurposing of Kinase Inhibitors for Treatment of COVID-19. Pharm Res. 2020; 37(9):167. PMC: 7417114. DOI: 10.1007/s11095-020-02851-7. View

19.

George P, Wells A, Gisli Jenkins R . Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020; 8(8):807-815. PMC: 7228727. DOI: 10.1016/S2213-2600(20)30225-3. View

20.

Chiok K, Hutchison K, Miller L, Bose S, Miura T . Proinflammatory Responses in SARS-CoV-2 and Soluble Spike Glycoprotein S1 Subunit Activated Human Macrophages. Viruses. 2023; 15(3). PMC: 10052676. DOI: 10.3390/v15030754. View