Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus

Hirayama, Takehiro; Konaka, Hachiro; Kato, Yasuhiro; Shibahara, Takayuki; Nishizawa, Chisato; Tsujimoto, Kohei; Park, Jeong Hoon; Itotagawa, Eri; Jo, Tatsunori; Nishide, Masayuki; Nishida, Sumiyuki; Shima, Yoshihito; Narazaki, Masashi; Aoki, Wataru; Ishii, Ken J.; Takamatsu, Hyota; Kumanogoh, Atsushi

doi:https://doi.org/10.1002/art.43434

Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus

Hirayama, Takehiro; Konaka, Hachiro; Kato, Yasuhiro et al.

Arthritis and Rheumatology, 2025, 78(4), 880-895

アクセス数:34件（2026-05-28 03:51 集計）

固定URL: https://hdl.handle.net/11094/104618

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タイトル	Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus
著者	著者名 Hirayama, Takehiro
	NRID 1000021019143 1000021019143 researchmap permalink 8657 8657 Scopus Author ID 57220390428 57220390428 著者名 Konaka, Hachiro
	NRID 1000030837050 1000030837050 ORCID 0000-0002-4050-2350 0000-0002-4050-2350 researchmap permalink katoY katoY Scopus Author ID 55473605900 55473605900 著者名 Kato, Yasuhiro
	著者名 Shibahara, Takayuki
	ORCID 0009-0003-3036-0293 0009-0003-3036-0293 researchmap permalink chisato_nishizawa chisato_nishizawa Scopus Author ID 59143149500 59143149500 著者名 Nishizawa, Chisato
	NRID 1000000965824 1000000965824 ORCID 0000-0001-6958-2983 0000-0001-6958-2983 researchmap permalink Kohei_Tsujimoto Kohei_Tsujimoto Scopus Author ID 57196317291 57196317291 著者名 Tsujimoto, Kohei
	著者名 Park, Jeong Hoon
	NRID 1000010973597 1000010973597 ORCID 0000-0003-0263-1108 0000-0003-0263-1108 researchmap permalink 50185058 50185058 Scopus Author ID 57208151838 57208151838 著者名 Itotagawa, Eri
	著者名 Jo, Tatsunori
	NRID 1000080812255 1000080812255 ORCID 0000-0001-6060-1228 0000-0001-6060-1228 researchmap permalink masayukinishide masayukinishide Scopus Author ID 37075377900 37075377900 著者名 Nishide, Masayuki
	NRID 1000000403189 1000000403189 researchmap permalink sumi_nishi_12 sumi_nishi_12 Scopus Author ID 55190147500 55190147500 著者名 Nishida, Sumiyuki
	NRID 1000090362706 1000090362706 ORCID 0000-0002-2523-2938 0000-0002-2523-2938 researchmap permalink read0106273 read0106273 Scopus Author ID 7102598347 7102598347 著者名 Shima, Yoshihito
	NRID 1000000467573 1000000467573 ORCID 0000-0002-5613-4409 0000-0002-5613-4409 researchmap permalink mnarazaki mnarazaki Scopus Author ID 7004556201 7004556201 著者名 Narazaki, Masashi
	NRID 1000010722184 1000010722184 ORCID 0000-0002-3118-9390 0000-0002-3118-9390 researchmap permalink 7000011391 7000011391 著者名 Aoki, Wataru
	著者名 Ishii, Ken J.
	NRID 1000030584411 1000030584411 ORCID 0000-0002-0382-5142 0000-0002-0382-5142 researchmap permalink thyota thyota Scopus Author ID 8935909000 8935909000 著者名 Takamatsu, Hyota
	NRID 1000010294125 1000010294125 ORCID 0000-0003-4749-7117 0000-0003-4749-7117 researchmap permalink read0051725 read0051725 Scopus Author ID 6602726311 6602726311 著者名 Kumanogoh, Atsushi
内容	Hirayama T., Konaka H., Kato Y., et al. Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus. Arthritis and Rheumatology 78, 880 (2026); https://doi.org/10.1002/art.43434.
抄録	Objective: Systemic lupus erythematosus (SLE) is characterized by increased Type I interferon (IFN-I) and autoantibody production. This study aimed to identify drugs that can inhibit both IFN-I and autoantibody production. Methods: We identified an inhibitor of IFN-I production from a chemical library. Subsequently, we examined its efficacy and underlying mechanisms in suppressing the expression and phosphorylation of upstream signaling molecules for IFN-I production and the differentiation of B cells into plasma cells. Additionally, we examined whether it could alleviate disease severity in SLE-prone mice. Results: We showed that vorinostat, a clinically approved pan-histone deacetylase (HDAC) inhibitor, inhibited both IFN-I production and plasma cell differentiation. Vorinostat suppressed IFN-I production by inhibiting TBK1 phosphorylation and the subsequent IRF3 nuclear translocation and suppressed plasma cell differentiation by inhibiting the expression of essential transcriptional factors for plasma cells. Notably, inhibiting HDAC6 suppressed IFN-I induction and plasma cell differentiation. Furthermore, vorinostat ameliorated lung inflammation in STING-associated vasculopathy with onset in infancy mice by decreasing IFN-I and alleviated the mortality and severity of renal disease in New Zealand Black/White F1 mice by suppressing IFN-I induction and B cell differentiation. Conclusion: Vorinostat ameliorates the severity of disease in SLE-prone mice by simultaneously suppressing IFN-I production and plasma cell differentiation by targeting HDAC6. Thus, vorinostat is a promising therapeutic agent for SLE and may benefit patients with SLE requiring more effective and better-tolerated therapies.
出版者	John Wiley and Sons Inc
収録物名	Arthritis and Rheumatology
巻(号)	78(4)
ページ	880-895
刊行年月	2025-11-14
言語	英語
ハンドルURL	https://hdl.handle.net/11094/104618
PISSN	23265191
eISSN	23265205
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1002/art.43434
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Arthritis and Rheumatology. 2025, 78(4), p. 880-895
DC.title	Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus
DC.creator	Hirayama, Takehiro
	Konaka, Hachiro
	Kato, Yasuhiro
	Shibahara, Takayuki
	Nishizawa, Chisato
	Tsujimoto, Kohei
	Park, Jeong Hoon
	Itotagawa, Eri
	Jo, Tatsunori
	Nishide, Masayuki
	Nishida, Sumiyuki
	Shima, Yoshihito
	Narazaki, Masashi
	Aoki, Wataru
	Ishii, Ken J.
	Takamatsu, Hyota
	Kumanogoh, Atsushi
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-11-14
DC.identifier	https://doi.org/10.1002/art.43434
DC.description	Hirayama T., Konaka H., Kato Y., et al. Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus. Arthritis and Rheumatology 78, 880 (2026); https://doi.org/10.1002/art.43434.
DCTERMS.abstract	Objective: Systemic lupus erythematosus (SLE) is characterized by increased Type I interferon (IFN-I) and autoantibody production. This study aimed to identify drugs that can inhibit both IFN-I and autoantibody production. Methods: We identified an inhibitor of IFN-I production from a chemical library. Subsequently, we examined its efficacy and underlying mechanisms in suppressing the expression and phosphorylation of upstream signaling molecules for IFN-I production and the differentiation of B cells into plasma cells. Additionally, we examined whether it could alleviate disease severity in SLE-prone mice. Results: We showed that vorinostat, a clinically approved pan-histone deacetylase (HDAC) inhibitor, inhibited both IFN-I production and plasma cell differentiation. Vorinostat suppressed IFN-I production by inhibiting TBK1 phosphorylation and the subsequent IRF3 nuclear translocation and suppressed plasma cell differentiation by inhibiting the expression of essential transcriptional factors for plasma cells. Notably, inhibiting HDAC6 suppressed IFN-I induction and plasma cell differentiation. Furthermore, vorinostat ameliorated lung inflammation in STING-associated vasculopathy with onset in infancy mice by decreasing IFN-I and alleviated the mortality and severity of renal disease in New Zealand Black/White F1 mice by suppressing IFN-I induction and B cell differentiation. Conclusion: Vorinostat ameliorates the severity of disease in SLE-prone mice by simultaneously suppressing IFN-I production and plasma cell differentiation by targeting HDAC6. Thus, vorinostat is a promising therapeutic agent for SLE and may benefit patients with SLE requiring more effective and better-tolerated therapies.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	104618
citation_title	Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus
citation_author	Hirayama, Takehiro
	Konaka, Hachiro
	Kato, Yasuhiro
	Shibahara, Takayuki
	Nishizawa, Chisato
	Tsujimoto, Kohei
	Park, Jeong Hoon
	Itotagawa, Eri
	Jo, Tatsunori
	Nishide, Masayuki
	Nishida, Sumiyuki
	Shima, Yoshihito
	Narazaki, Masashi
	Aoki, Wataru
	Ishii, Ken J.
	Takamatsu, Hyota
	Kumanogoh, Atsushi
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2025-11-14
citation_journal_title	Arthritis and Rheumatology
citation_volume	78
citation_issue	4
citation_firstpage	880
citation_lastpage	895
citation_doi	https://doi.org/10.1002/art.43434
citation_public_url	https://hdl.handle.net/11094/104618

Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus

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