Desmethoxycurcumin aids IFNα’s anti-HBV activity by antagonising CRYAB reduction and stabilising IFNAR1 protein

AbstractThe eradication of chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) infection is a crucial goal in clinical practice. Enhancing the anti-HBV activity of interferon type I (IFNI) is a key strategy for achieving a functional cure for CHB. In this study, we investigated the effect of combined treatment with IFNα and Desmethoxycurcumin (DMC) on HBV replication in HepG2 cells and explored the underlying mechanism. Our results indicated IFNα alone was ineffective in completely inhibiting HBV replication, which was attributed to the virus-induced down-regulation of IFNI receptor 1 (IFNAR1) protein. However, the addition of a low dose of DMC significantly synergized with IFNα, leading to notable enhancement of IFNα anti-HBV activity. This effect was achieved by stabilising the IFNAR1 protein. Further investigation revealed that low dose DMC effectively blocked the ubiquitination-mediated degradation of IFNAR1, which was accomplished by rescuing the protein levels of alphaB-crystallin (CRYAB) and orchestrating the interaction between CRYAB and the E3 ubiquitin ligase, β-Trcp. Importantly, over-expression of CRYAB was found to favour the antiviral activity of IFNα against HBV replication. In conclusion, our study demonstrates that low-dose DMC enhanced the anti-HBV activity of IFNα by counteracting the reduction of CRYAB and stabilising the IFNAR1 protein.Keywords: DMCIFNAR1 degradationantagonizecRYABHBV immune escape AcknowledgementsWe gratefully thank American Journal Experts for editing this manuscript.Ethical approvalNo animal studies are presented in this manuscript. No human studies are presented in this manuscript. No potentially identifiable human images or data are presented in this study.Author contributionsT.T.C., Q.X., and X.C.D. designed the experiments. X.Y.L., G.Y.Z., and X.Y.F. performed the bioinformatic analysis. W.Y.D., L.X.X., and J.L.W. performed the experiments. J.L.W. wrote the paper and modified it for the final version of the manuscript. All authors read and approved the manuscript.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThis study did not include data deposited in external repositories. All relevant data are available in the manuscript and Supporting Information files.Additional informationFundingThis study was supported by the Science and Technology Planning Project of Yuzhong District of Chongqing City (2020050), the Chongqing Municipal Education Commission Foundation (KJQN202000403), General project of Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0095), and Chongqing Medical University Undergraduate Innovation Experiment Project (approval numbers LTMCMTS202121, LTMCMTS202221, and LTMCMTS202222).