1. World Health Organization. Hepatitis B fact sheets. World Health Organization;
2022.
2. Ohishi W, Chayama K. Treatment of chronic hepatitis B with nucleos(t)ide analogues. Hepatol Res. 2012;42:219–25.
3. Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology.
2009;49:S103–111.
4. Lee HW, Lee JS, Ahn SH. Hepatitis B Virus cure: targets and future therapies. Int J
Mol Sci. 2020;22:213.
5. Stadler D, Kächele M, Jones AN, Hess J, Urban C, Schneider J, et al. Interferoninduced degradation of the persistent hepatitis B virus cccDNA form depends on
ISG20. EMBO Rep. 2021;22:e49568.
6. Amin OE, Colbeck EJ, Daffis S, Khan S, Ramakrishnan D, Pattabiraman D, et al.
Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic
hepatitis B: re-modelling of antiviral and regulatory mediators. Hepatology.
2020;75:54–71.
7. Furutani Y, Toguchi M, Shiozaki-Sato Y, Qin XY, Ebisui E, Higuchi S, et al. An
interferon-like small chemical compound CDM-3008 suppresses hepatitis B virus
through induction of interferon-stimulated genes. PLoS ONE. 2019;14:e0216139.
8. Ito K, Okumura A, Takeuchi JS, Watashi K, Inoue R, Yamauchi T, et al. Dual agonist
of farnesoid X receptor and Takeda G protein-coupled receptor 5 inhibits
Hepatitis B virus infection in vitro and in vivo. Hepatology. 2021;74:83–98.
9. Niu C, Li L, Daffis S, Lucifora J, Bonnin M, Maadadi S, et al. Toll-like receptor 7
agonist GS-9620 induces prolonged inhibition of HBV via a type I interferondependent mechanism. J Hepatol. 2018;68:922–31.
10. Konishi H, Okamoto K, Ohmori Y, Yoshino H, Ohmori H, Ashihara M, et al. An
orally available, small-molecule interferon inhibits viral replication. Sci Rep.
2012;2:259.
11. Furutani Y, Toguchi M, Higuchi S, Yanaka K, Gailhouste L, Qin XY, et al. Establishment of a rapid detection system for ISG20-dependent SARS-CoV-2 subreplicon RNA degradation induced by interferon-α. Int J Mol Sci. 2021;22:11641.
12. Kueck T, Cassella E, Holler J, Kim B, Bieniasz PD. The aryl hydrocarbon receptor
and interferon gamma generate antiviral states via transcriptional repression.
Elife. 2018;7:e38867.
13. Hu J, Qiao M, Chen Y, Tang H, Zhang W, Tang D, et al. Cyclin E2-CDK2 mediates
SAMHD1 phosphorylation to abrogate its restriction of HBV replication in
hepatoma cells. FEBS Lett. 2018;592:1893–904.
14. Jeong GU, Park IH, Ahn K, Ahn BY. Inhibition of hepatitis B virus replication by a
dNTPase-dependent function of the host restriction factor SAMHD1. Virology.
2016;495:71–78.
15. Sommer AF, Rivière L, Qu B, Schott K, Riess M, Ni Y, et al. Restrictive influence of
SAMHD1 on Hepatitis B Virus life cycle. Sci Rep. 2016;6:26616.
16. Ohashi H, Nishioka K, Nakajima S, Kim S, Suzuki R, Aizaki H, et al. The aryl
hydrocarbon receptor-cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly. J Biol Chem.
2018;293:19559–71.
17. Nakano M, Fukami T, Gotoh S, Takamiya M, Aoki Y, Nakajima M. RNA editing
modulates human hepatic aryl hydrocarbon receptor expression by creating
MicroRNA recognition sequence. J Biol Chem. 2016;291:894–903.
18. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and
nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science.
2014;343:1221–8.
Cell Death Discovery (2023)9:467
Y. Furutani et al.
13
19. Xia Y, Stadler D, Lucifora J, Reisinger F, Webb D, Hösel M, et al. Interferon-γ and
tumor necrosis factor-α produced by T cells reduce the HBV persistence Form,
cccDNA, without cytolysis. Gastroenterology. 2016;150:194–205.
20. Berke JM, Dehertogh P, Vergauwen K, Mostmans W, Vandyck K, Raboisson P, et al.
Antiviral properties and mechanism of action studies of the Hepatitis B virus capsid
assembly modulator JNJ-56136379. Antimicrob Agents Chemother. 2020;64.
21. Huang Q, Cai D, Yan R, Li L, Zong Y, Guo L, et al. Preclinical profile and characterization of the Hepatitis B virus core protein inhibitor ABI-H0731. Antimicrob
Agents Chemother. 2020;64:e01463-20.
22. Dong C, Qu L, Wang H, Wei L, Dong Y, Xiong S. Targeting hepatitis B virus cccDNA
by CRISPR/Cas9 nuclease efficiently inhibits viral replication. Antivir Res.
2015;118:110–7.
23. Sakai M, Takahashi N, Ikeda H, Furutani Y, Higuchi S, Suzuki T, et al. Design,
synthesis, and target identification of new hypoxia-inducible factor 1 (HIF-1)
inhibitors containing 1-alkyl-1H-pyrazole-3-carboxamide moiety. Bioorg Med
Chem. 2021;46:116375.
24. Wing PAC, Liu PJ, Harris JM, Magri A, Michler T, Zhuang X, et al. Hypoxia inducible
factors regulate hepatitis B virus replication by activating the basal core promoter. J Hepatol. 2021;75:64–73.
25. Thomas C, Moraga I, Levin D, Krutzik PO, Podoplelova Y, Trejo A, et al. Structural
linkage between ligand discrimination and receptor activation by type I interferons. Cell. 2011;146:621–32.
26. Schrödinger Release 2014-1. Maestro. New York, NY: Schrödinger, LLC; 2014.
27. Schrödinger Release 2014-1. Epick. New York, NY: Schrödinger, LLC; 2014.
28. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a
genetic algorithm for flexible docking. J Mol Biol. 1997;267:727–48.
29. Schrödinger Release 2014-1. Glide. New York, NY: Schrödinger, LLC; 2014.
30. Molecular Operating Environment (MOE). 1010 Sherbooke St. West, Suite #910,
Montreal, QC, Canada, H3A 2R7: 2014.01 Chemical Computing Group ULC; 2014.
31. Watanabe T, Sudoh M, Miyagishi M, Akashi H, Arai M, Inoue K, et al. Intracellulardiced dsRNA has enhanced efficacy for silencing HCV RNA and overcomes variation in the viral genotype. Gene Ther. 2006;13:883–92.
32. Ishida Y, Yamasaki C, Yanagi A, Yoshizane Y, Fujikawa K, Watashi K, et al. Novel
robust in vitro hepatitis B virus infection model using fresh human hepatocytes
isolated from humanized mice. Am J Pathol. 2015;185:1275–85.
33. Sugiyama M, Tanaka Y, Kato T, Orito E, Ito K, Acharya SK, et al. Influence of
hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA
and antigens. Hepatology. 2006;44:915–24.
34. Zhang Y, Wolf-Yadlin A, Ross PL, Pappin DJ, Rush J, Lauffenburger DA, et al. Timeresolved mass spectrometry of tyrosine phosphorylation sites in the epidermal
growth factor receptor signaling network reveals dynamic modules. Mol Cell
Proteom. 2005;4:1240–50.
35. Potel CM, Lemeer S, Heck AJR. Phosphopeptide fragmentation and site localization by mass spectrometry: an update. Anal Chem. 2019;91:126–41.
36. Taus T, Kocher T, Pichler P, Paschke C, Schmidt A, Henrich C, et al. Universal and
confident phosphorylation site localization using phosphoRS. J Proteome Res.
2011;10:5354–62.
37. Qin XY, Hara M, Arner E, Kawaguchi Y, Inoue I, Tatsukawa H, et al. Transcriptome
analysis uncovers a growth-promoting activity of Orosomucoid-1 on hepatocytes.
EBioMedicine. 2017;24:257–66.
38. Fonsi M, Orsale MV, Monteagudo E. High-throughput microsomal stability assay
for screening new chemical entities in drug discovery. J Biomol Screen.
2008;13:862–9.
We also thank Chiemi Mishima-Tsumagari and Miyuki Kato-Murayama for protein
purification and Shuji Kobayashi for AhR signal analysis. HepG2-NTCP-C4 cells were
kindly gifted from Drs. Koichi Watashi and Takaji Wakita (NIID). This manuscript is
dedicated to the memory of Dr. Soichi Kojima (1961–2019).
AUTHOR CONTRIBUTIONS
Y.F.: Methodology, Data curation, Formal analysis, Investigation, Writing—original
draft, Funding acquisition,; XY.Q., Y.H., M.K.-N.: Data curation Investigation, Writing—
original draft; N.D., M.S., S.N. M.S., S.N., H.S., K.K., T.Masaki, H.K.: Methodology,
Supervision, Investigation, Writing—original draft; M.T., S.H., K.Y., Y. SS, N.T., M.S., P.K.,
T.S. K.S., M.O., K.K.: Data curation, Investigation; M.K.: Resources; S.K., H.K., T.Matsuura:
Methodology, Supervision, Writing - review and editing, Funding acquisition, Project
administration.
FUNDING
This work was mainly supported by AMED under Grant Number JP21fk0310112
(T.Matsuura, Y.F., Y.H., N.D., M.S., S.N., H.S., K.K., T.Masaki, H.K.) and 22fk0210112 (Y.F.)
and partly supported by Grant Number 22fk0310511 (Y.F.) and 22fk0210100 (Y.F.) and
a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan [17H06401 (H.K.), 23H04882 (H.K.)].
COMPETING INTERESTS
The authors declare no competing interests.
ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41420-023-01755-w.
Correspondence and requests for materials should be addressed to Yutaka Furutani.
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ACKNOWLEDGEMENTS
The authors thank members of Department of Laboratory Medicine and Liver Cancer
Prevention Research Unit for kind discussion and technical and secretarial assistance.
Cell Death Discovery (2023)9:467
© The Author(s) 2023
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