Research on Necroptosis Inhibition: Novel Therapeutics for Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

Research Identifies and Inhibits Key Cell Death Pathway in Severe Cutaneous Adverse Reactions

A collaborative team of Japanese researchers has made a major breakthrough in the treatment of severe cutaneous adverse reactions, such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), diseases that carry a mortality rate of approximately 30%. Led by Haruna Kimura, Dr. Akito Hasegawa, Prof. Riichiro Abe, alongside Prof. Takemasa Ozawa and Dr. Yoichi Ogawa, the team has developed a novel therapeutic candidate targeting necroptosis, a programmed cell death pathway implicated in the pathogenesis of SJS/TEN. Their findings were recently published in Nature Communications on September 30, 2025.

SJS and TEN are often triggered by drug administration and characterized by extensive erosion of the skin and mucous membranes. Current treatments include systemic corticosteroids as first-line therapy, with intravenous immunoglobulin or plasma exchange used in refractory cases. Despite these interventions, about 30% of patients still experience fatal outcomes, highlighting the urgent need for more effective therapies.

Previous research by this group revealed that necroptosis occurs in keratinocytes within SJS/TEN lesions and is mediated through formyl peptide receptor 1 (FPR1), a receptor expressed on epidermal cells. Necroptosis, a type of programmed cell death distinct from apoptosis, contributes to the rapid destruction of skin tissues in SJS/TEN, worsening patient outcomes.

Building on these insights, the team developed a screening system to identify compounds with strong FPR1 inhibitory activity. Using SJS/TEN model cells, they tested candidate compounds for their ability to suppress necroptosis and discovered that certain FPR1 inhibitors effectively reduced cell death and prevented disease onset in model mice.

The compound screening leveraged the Drug Discovery Initiative at The University of Tokyo, which houses a comprehensive library of potential therapeutic agents. FPR1 is a G protein–coupled receptor (GPCR), signaling through both G proteins and β-arrestins. Prof. Ozawa’s group had previously developed assays capable of detecting these distinct signaling pathways independently, allowing for precise identification of effective FPR1 inhibitors.

Through this approach, the researchers selected two novel candidate compounds with high FPR1 inhibitory activity. In addition, five previously reported FPR1 inhibitors were included as reference candidates. These compounds demonstrated potent suppression of necroptosis in SJS/TEN model cells, indicating their potential as therapeutic agents for preventing severe cutaneous adverse reactions.

Lead author Haruna Kimura commented,

“By identifying and inhibiting the FPR1-mediated necroptosis pathway, we have opened a new avenue for treating SJS/TEN. Our findings show that blocking this pathway can protect keratinocytes from programmed cell death, which is critical in these life-threatening skin conditions.”

Prof. Riichiro Abe added,

“The urgent need for novel SJS/TEN therapies cannot be overstated. Current treatments are not always sufficient, and approximately one-third of patients succumb to the disease. Our discovery of FPR1 inhibitors provides hope for a more effective and targeted therapy.”

This research represents a significant step forward in dermatology and drug discovery, as it combines molecular pathway elucidation with practical therapeutic applications. The use of model cells and animal studies provides strong preclinical evidence for the potential clinical translation of FPR1 inhibitors.

In addition to their efficacy, these compounds could be integrated with current SJS/TEN therapies, such as corticosteroids or immunoglobulin therapy, to enhance outcomes while potentially reducing toxicity. The team aims to advance these inhibitors into preclinical and clinical trials, with the long-term goal of improving prognosis and survival rates in patients suffering from these severe cutaneous adverse reactions.

Research Reference

Kimura H, Hasegawa A, Abe R, Ozawa T, Ogawa Y. FPR1-mediated necroptosis as a therapeutic target in Stevens–Johnson syndrome and toxic epidermal necrolysis. Nature Communications. 2025;16:5563. doi:10.1038/s41467-025-5563-2
(Demonstrates the role of necroptosis and FPR1 in severe cutaneous adverse reactions and identifies potential therapeutic inhibitors.)