Potential therapy for lethal drug-induced skin reactions?

The FPR1-inhibitory activity of the candidate compounds was evaluated using an in vitro SJS/TEN assay. Cell death inhibition was assessed by live/dead staining following treatment with various concentrations of each compound. Among the seven candidates, CDCA exhibited a specific and potent inhibitory effect on cell death, even at low concentrations. Image modified from Kimura H et al., Nat Commun. 2025.

A Japanese research group has identified a promising therapeutic candidate for two of dermatology’s most severe and life‑threatening conditions—Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The findings, published September 30 in Nature Communications, describe how inhibition of a receptor driving keratinocyte cell death could prevent disease onset in preclinical models.

Led by Haruna Kimura, Dr. Akito Hasegawa, and Professor Riichiro Abe of the Division of Dermatology at Niigata University Graduate School of Medical and Dental Sciences, the group collaborated with Professor Takemasa Ozawa of the University of Tokyo and Dr. Yoichi Ogawa of the University of Yamanashi. Their work builds on earlier studies implicating necroptosis—a regulated form of cell death mediated through formyl peptide receptor 1 (FPR1)—in the epidermal damage characteristic of SJS/TEN.

SJS and TEN are triggered by adverse drug reactions and characterized by widespread epidermal detachment and mucosal erosion. Despite interventions that include systemic corticosteroids, intravenous immunoglobulin, or plasma exchange, mortality rates remain around 30%. “The urgent need for more effective treatments has driven our search for molecular targets that control keratinocyte death,” said Dr. Hasegawa.

Using chemical library resources from the University of Tokyo’s Drug Discovery Initiative, the team screened for compounds with high FPR1 inhibitory activity. FPR1, a G protein–coupled receptor engaged in both G protein and β‑arrestin signalling, was assessed through dual‑pathway assays developed by Professor Ozawa’s laboratory. Among several candidates, chenodeoxycholic acid (CDCA) emerged as a potent inhibitor of FPR1‑mediated signalling.

In vitro, CDCA effectively suppressed keratinocyte necroptosis induced by annexin A1–FPR1 interactions. In a humanized mouse model exhibiting SJS/TEN‑like pathology, CDCA treatment reduced epidermal and conjunctival cell death and prevented disease emergence. “Chenodeoxycholic acid completely suppressed disease‑like symptoms in preclinical models,” the authors wrote, noting the strong translational potential of FPR1 inhibition as a therapeutic strategy.

While additional pharmacologic validation and clinical trials are needed, the discovery positions FPR1 blockade as a potential breakthrough in managing SJS/TEN, conditions that often leave survivors with lasting ocular and mucosal injury. Professor Abe highlighted the translational significance in a press release: “Our findings provide a foundation for developing first‑in‑class therapeutics targeting necroptosis in cutaneous drug reactions.”

The study underscores a growing recognition that modulating programmed cell death may redefine strategies for rescuing patients from otherwise fatal dermatologic emergencies.