Targeting Regulated Cell-Death Pathways in Severe Cutaneous Adverse Reactions

Investigators have linked formyl peptide receptor 1 (FPR1)–dependent necroptosis to epidermal cell death in SJS/TEN–type reactions and described an FPR1-targeted inhibitor that reduced tissue injury in preclinical models, pointing to a mechanistically targeted approach where options are currently limited.

Stevens-Johnson syndrome and toxic epidermal necrolysis have long been associated with immune-mediated keratinocyte death but lacked a clear receptor-level target amenable to small-molecule therapy. Current management remains primarily supportive and immunomodulatory, and mortality in the most severe cases can approach 30%. Identifying a receptor on epidermal cells reframes treatments from broadly immunosuppressive strategies toward mechanism-directed intervention.

The investigators describe a pathway in which keratinocyte FPR1, when engaged by immune-derived triggers, initiates a necroptotic cascade that ends in membrane rupture and cell loss; they specifically connect this cascade to cytotoxic lymphocyte products and danger-associated molecular signals observed in lesional skin.

Clinicians and investigators should watch for investigator-initiated and industry-sponsored phase 1 studies that integrate lesion biomarker assessment with clinical endpoints in carefully selected severe cutaneous adverse reaction cases.