Can spatial proteomics find a TEN therapy?
Deep visual proteomics of drug-reaction skin (>5,000 proteins/cell type) revealed interferon–STAT1 programs in TEN; JAK inhibitors improved disease in mouse models.
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Spatial proteomics identifies JAKi as treatment for a lethal skin disease
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Can spatial proteomics find a TEN therapy?
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More than 5,000 proteins quantified per cell type compartment.
We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells.
Primary DVP cohort n=21 (5 DRESS, 5 MPR, 5 healthy, 6 TEN).
a , Top, schematic of the DVP workflow for cell-type-resolved proteomics in CADRs ( n = 21; 5 each for DRESS, MPR and healthy, and 6 for TEN).
What they did
Used deep visual proteomics on archived FFPE biopsies across CADR severities to quantify keratinocyte and immune-cell proteomes, then tested oral JAKis in two TEN mouse models.
What they found
TEN showed enriched type I/II interferon signatures and phosphorylated STAT1. Tofacitinib, baricitinib, abrocitinib, or upadacitinib ameliorated clinical/histological severity in mice. TEN involves >30% epidermal detachment and lacked effective therapy.
The limits
What it doesn't show
Mouse efficacy and proteomic nomination are not a completed large randomized TEN trial; dosing/safety in critically ill TEN patients need careful clinical evaluation.
Key terms
- TEN
- Toxic epidermal necrolysis: severe drug reaction with >30% epidermal detachment.
- Deep visual proteomics (DVP)
- Imaging + AI cell picking + ultrasensitive MS proteomics at cell-type resolution.
- JAKi
- JAK inhibitors (e.g., tofacitinib, baricitinib, abrocitinib, upadacitinib).
- STAT1
- Transcription factor phosphorylated downstream of interferon signalling in TEN.
- CADR
- Cutaneous adverse drug reaction spectrum from MPR to DRESS/SJS/TEN.
- DRESS
- Drug reaction with eosinophilia and systemic symptoms; comparator severe CADR.
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Proteins quantified were more than:
Common questions
How many proteins quantified?
More than 5,000 in keratinocytes and skin-infiltrating immune cells.
DVP cohort makeup?
n=21: 5 DRESS, 5 MPR, 5 healthy, 6 TEN.
Key pathway hit?
Type I/II interferon signatures with pSTAT1.
Drug class tested?
JAK inhibitors including tofacitinib/baricitinib/abrocitinib/upadacitinib.