ORIGINAL RESEARCH article

Front. Bioeng. Biotechnol.

Sec. Cell and Gene Therapy

Volume 13 - 2025 | doi: 10.3389/fbioe.2025.1639869

This article is part of the Research TopicBioengineering Strategies Targeting Emerging Cell Death Modalities in Chronic Non-Communicable DiseasesView all articles

Comprehensive Analysis of Pyroptosis-Related Genes in Psoriasis and Targeted Gene Editing of CASP1 and CASP5 Using Lipid Nanoparticles to Alleviate Skin Inflammation

Provisionally accepted
Gexiao  XuGexiao Xu1Guanyi  MaGuanyi Ma2Jiachen  SunJiachen Sun3Xiaoyan  YuXiaoyan Yu1Jie  SunJie Sun1Bing  GaoBing Gao4*
  • 1Department of Dermatology, Dermatology Hospital of Xiaoshan District, Hangzhou, China
  • 2the 988th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Zhengzhou, China
  • 3Peking University Third Hospital, Beijing, China
  • 4Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China

The final, formatted version of the article will be published soon.

Psoriasis is a chronic inflammatory skin disorder driven by immune dysregulation and excessive cell death. Pyroptosis, a form of inflammatory programmed cell death, has not been extensively studied in the context of psoriasis despite its importance in inflammation. In this study, we systematically analyzed the expression of pyroptosisrelated genes (PRGs) in psoriasis to identify critical players involved in disease progression. Using bioinformatics tools and publicly available datasets, we constructed a risk score model based on machine learning algorithms, which identified several key hub genes including CASP1, CASP5, AIM2, GZMB, GZMA, IL1B, and NOD2. The generated risk score model demonstrated robust performance in external validation datasets, showing strong predictive power for psoriasis severity and immune infiltration.High-risk patients exhibited increased inflammatory cell infiltration and worsening clinical symptoms, which was consistent with the model's ability to predict immune response dynamics in psoriatic lesions. To further validate our findings, we analyzed single-cell RNA sequencing data and demonstrated that the risk score was highly correlated with immune cell composition, particularly DCs, T cells, and mast cells, indicating that patients with higher risk scores have more severe disease and stronger immune infiltration. Additionally, we targeted CASP1 and CASP5 using CRISPR-Cas9 delivery via lipid nanoparticles (LNPs) to selectively knock out these genes in keratinocytes, resulting in significant therapeutic effects in the IMQ-induced psoriasis mouse model. Our findings provide comprehensive insights into the role of pyroptosis in psoriasis and propose a novel gene editing strategy for alleviating the disease.

Keywords: Psoriasis, pyroptosis, Immune infiltration, risk score, Lipid nanoparticles, CRISPR-Cas9

Received: 02 Jun 2025; Accepted: 08 Jul 2025.

Copyright: © 2025 Xu, Ma, Sun, Yu, Sun and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Bing Gao, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China

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