Available online 28 November 2023

Author links open overlay panel, , , , , , , Highlights•

PANoptosis signature in psoriasis was highlighted.

•

PANoptosis signaling elicits an immune response that contributes to psoriatic pathogenesis.

•

Based on PANoptosis-mediated immune signaling, disulfiram was predicted to be a potential drug for psoriasis.

•

Disulfiram ameliorates IMQ-mediated psoriatic lesions through EGF signaling.

AbstractBackground

Accumulating evidence suggests that regulated cell death, such as pyroptosis, apoptosis, and necroptosis, is deeply involved in the pathogenesis of psoriasis. As a newly recognized form of systematic cell death, PANoptosis is involved in a variety of inflammatory disorders through amplifying inflammatory and immune cascades, but its role in psoriasis remains elusive.

Objectives

To reveal the role of PANoptosis in psoriasis for a potential therapeutic strategy.

Methods

Multitranscriptomic analysis and experimental validation were used to identify PANoptosis signaling in psoriasis. RNA-seq and scRNA-seq analyses were performed to establish a PANoptosis-mediated immune response in psoriasis, which revealed hub genes through WGCNA and predicted disulfiram as a potential drug. The effect and mechanism of disulfiram were verified in imiquimod (IMQ)-induced psoriasis.

Results

Here, we found a highlighted PANoptosis signature in psoriasis patients through multitranscriptomic analysis and experimental validation. Based on this, two distinct PANoptosis patterns (non/high) were identified, which were the options for clinical classification. The high-PANoptosis-related group had a higher response rate to immune cell infiltration (such as M1 macrophages and keratinocytes). Subsequently, WGCNA showed the hub genes (e.g., S100A12, CYCS, NOD2, STAT1, HSPA4, AIM2, MAPK7), which were significantly associated with clinical phenotype, PANoptosis signature, and identified immune response in psoriasis. Finally, we explored disulfiram (DSF) as a candidate drug for psoriasis through network pharmacology, which ameliorated IMQ-mediated psoriatic symptoms through antipyroptosis-mediated inflammation and enhanced apoptotic progression. By analyzing the specific ligandreceptor interaction pairs within and between cell lineages, we speculated that DSF might exert its effects by targeting keratinocytes directly or targeting M1 macrophages to downregulate the proliferation of keratinocytes.

Conclusions

PANoptosis with its mediated immune cell infiltration provides a roadmap for research on the pathogenesis and therapeutic strategies of psoriasis.

AbbreviationsALDH

aldehyde dehydrogenase

DAMPs

damage-associated molecular patterns

DEG

differentially expressed gene

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

ERBB2

erythroblastic leukemia viral oncogene homolog-2

FDA

Food and Drug Administration

GSEA

gene set enrichment analysis

GSVA

gene set variation analysis

KEGG

Kyoto Encyclopedia of Genes and Genomes

MSCs

mesenchymal stem cells

Nec-1s

RIPK1 R-7-Cl-O-Necrostatin-1

NSA

MLKL-inhibitor necrosulfonamide

PASI

Psoriasis Area and Severity Index

PCA

principal component analysis

scRNA-seq

single-cell sequencing data

TUNEL

terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

ZBP1

Z-DNA binding protein 1

Keywords

PANoptosis

pyroptosis

psoriasis

immune

disulfiram

network pharmacology

© 2023 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.