Inhibition of formyl peptide receptor-1-mediated cell death as a therapy for lethal cutaneous drug reactions in preclinical models

Haruna Kimura, Akito Hasegawa (), Tomoki Nishiguchi, Hong Ha Nguyen, Masatoshi Eguchi, Manao Kinoshita, Youichi Ogawa, Takeaki Ozawa () and Riichiro Abe ()
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Haruna Kimura: Niigata University Graduate School of Medical and Dental Sciences; Niigata
Akito Hasegawa: Niigata University Graduate School of Medical and Dental Sciences; Niigata
Tomoki Nishiguchi: Niigata University Graduate School of Medical and Dental Sciences; Niigata
Hong Ha Nguyen: Niigata University Graduate School of Medical and Dental Sciences; Niigata
Masatoshi Eguchi: Niigata University Graduate School of Medical and Dental Sciences; Niigata
Manao Kinoshita: University of Yamanashi
Youichi Ogawa: University of Yamanashi
Takeaki Ozawa: The University of Tokyo; Hongo
Riichiro Abe: Niigata University Graduate School of Medical and Dental Sciences; Niigata

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Stevens-Johnson syndrome and toxic epidermal necrolysis are life-threatening mucocutaneous adverse drug reactions characterized by disseminated skin and mucosal detachment. Mortality rates remain high and have increased in recent years, highlighting the need for effective therapeutic strategies. Programmed cell death, specifically necroptosis, induced by the interaction between annexin A1 and formyl peptide receptor-1 on the keratinocyte membrane, plays a critical role in disease pathogenesis. Here, we show that chenodeoxycholic acid, identified through chemical library screening for compounds that inhibit formyl peptide receptor 1-mediated signaling, effectively suppresses keratinocyte necroptosis. Chenodeoxycholic acid reduces keratinocyte cell death in vitro and completely suppresses disease-like symptoms in a humanized mouse model of Stevens-Johnson syndrome and toxic epidermal necrolysis, including a marked reduction in conjunctival cell death. These findings suggest that inhibition of formyl peptide receptor 1 with chenodeoxycholic acid represents a potential therapeutic strategy to improve outcomes in patients with these severe drug reactions, although further validation in clinical settings is required.

Date: 2025
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DOI: 10.1038/s41467-025-63744-0

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