PANoptosis signaling enables broad immune response in psoriasis: From pathogenesis to new therapeutic strategies

Xi-Min Hu; Shengyuan Zheng; Qi Zhang; Xinxing Wan; Ji Li; Rui Mao; Ronghua Yang; Kun Xiong

doi:10.1016/j.csbj.2023.11.049

PANoptosis signaling enables broad immune response in psoriasis: From pathogenesis to new therapeutic strategies

Comput Struct Biotechnol J. 2023 Nov 28:23:64-76. doi: 10.1016/j.csbj.2023.11.049. eCollection 2024 Dec.

Authors

Xi-Min Hu^{1

2}, Shengyuan Zheng¹, Qi Zhang², Xinxing Wan³, Ji Li^{1

4

5}, Rui Mao¹, Ronghua Yang⁶, Kun Xiong^{2

7

8}

Affiliations

¹ Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
² Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China.
³ Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
⁴ Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁵ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
⁶ Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510000, China.
⁷ Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁸ Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China.

Abstract

Background: 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 ligand-receptor 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.

Keywords: Disulfiram; Immune; Network pharmacology; PANoptosis; Psoriasis; Pyroptosis.