目的 基于基因调控网络分析银屑病中细胞焦亡相关基因的表达模式，并探讨其在银屑病的发生和发展中的作用，以寻找可能的治疗方案。方法 使用NCBI基因表达Omnibus数据库获取银屑病患者皮损区和非皮损区样本的基因表达数据集。利用limma算法筛选出差异表达基因（differentially expressed genes，DEGs），并运用WebGestalt对DEGs进行富集分析。收集与细胞焦亡和银屑病相关的共有基因，并利用GENIE3构建共有基因的上游转录调节网络。使用HERB和COREMINE数据库预测可能干预细胞焦亡和银屑病互作机制的中药和化学药。结果 在银屑病的发病过程中，包括半胱氨酸蛋白酶4/5/8（cysteinasparate protease 4/5/8，CASP4/5/8）在内的13个细胞焦亡基因参与了程序性细胞死亡的调节、蛋白酶活性的调控、内肽酶活性的调节以及白细胞介素-1β（interleukin-1β，IL-1β）的产生等过程。通过识别共享基因，发现这些基因的转录过程受到包括信号转导和转录激活因子3（signal transducer and activator of transcription 3，STAT3）和维生素D受体（vitamin D receptor，VDR）在内的54个转录因子的调控，共涉及64个转录调控关系。其中，转录因子VDR、钙调蛋白结合转录激活因子2（calmodulin binding transcription activator 2，CAMTA2）和锌指E盒结合同源盒蛋白2（zinc finger E-box binding homeobox 2，ZEB2）可能直接调节CASP8的转录过程，而转录因子STAT3、碱性亮氨酸拉链ATF样转录因子2（basic leucine zipper ATF-like transcription factor 2，BATF2）和催乳素调节元件结合蛋白（prolactin regulatory element binding，PREB）可能直接调节CASP4、CASP5的转录过程。此外，发现环孢素、甲氨蝶呤和异维A酸可能通过影响CASP4和CASP8基因的表达来逆转银屑病症状。基于银屑病细胞焦亡基因靶点预测得到99味核心中药，药味以苦、辛、甘为主，药性以寒、温、平为主，归经以肝、肺、脾经为主。结论 进一步丰富了以STAT3为中心的细胞焦亡调控银屑病发生机制的模型。发现VDR和ZEB2转录调节的STAT3-焦孔素E（gasdermin-E，GSDMEC）-CASP8通路以及STAT3-GSDMD-CASP4/5通路共同参与了细胞焦亡过程，并对角质形成细胞的分化和增殖产生影响。基于此通路寻找出作用于细胞焦亡过程的化学药和中药，为治疗银屑病提供新的解决方案。

Objective To analyze the expression patterns of pyroptosis-related genes in psoriasis based on the gene regulatory network (GRN) inference, and identify gene functions in the occurrence and development of psoriasis, so as to find potential therapeutic medicine candidates. METHODS NCBI Gene Expression Omnibus database was used to obtain a gene expression dataset of lesional and non-lesional samples from psoriasis patients. Subsequently, differentially expressed genes (DEGs) were screened out using the limma algorithm, and enrichment analysis was performed on the DEGs using WebGestalt. We collected the shared genes related to pyroptosis and psoriasis, and used GENIE3 to construct the upstream transcriptional regulation network of these shared genes. The HERB and COREMINE databases was used to predict the western and traditional Chinese medicines (TCMs) that might interfere with the interaction mechanism of pyroptosis and psoriasis. Results The research findings indicate the involvement of 13 cell death genes, including cysteinasparate protease 4/5/8 (CASP4/5/8), in the intricate processes of programmed cell death regulation, protease activity modulation, endopeptidase activity regulation, and interleukin-1β (IL-1β) production during the pathogenesis of psoriasis. By identifying shared genes, we found that the transcription process of these genes was regulated by 54 transcription factors (TFs) including signal transducer and activator of transcription 3 (STAT3) and vitamin D receptor (VDR), involving a total of 64 transcriptional regulatory relationships. Among them, transcription factors VDR, calmodulin binding transcription activator 2 (CAMTA2) and zinc finger E-box binding homeobox 2 (ZEB2) may directly regulate the transcription process of CASP8, while transcription factors STAT3, basic leucine zipper ATF-like transcription factor 2 (BATF2) and prolactin regulatory element binding (PREB) may directly regulate the transcription process of C CASP4, CASP5. In addition, we found that cyclosporine, methotrexate, and isotretinoin may reverse psoriasis symptoms by affecting the expression of CASP4 and CASP8 genes. Through the above studies, we have a deeper understanding of the expression patterns of pyroptosis-related genes in psoriasis, and revealed their role in the occurrence and development of psoriasis. In addition, we have proposed potential therapeutic approaches based on the prediction of pyroptosis gene targets in psoriasis. A total of 99 TCMs were identified, characterized by bitter, sweet, and pungent tastes. The medicinal properties primarily included cold, warm, and neutral attributes, while the liver, spleen and lung meridians were the main channels affected. These findings hold promise in providing novel insights and directions for the treatment of psoriasis. Conclusion We enriched the model of psoriasis pathogenesis, focusing on the pyroptosis regulation centered around STAT3. We identified that the STAT3-GSDMEC-CASP8 pathway regulated by VDR and ZEB2 transcription factors, as well as the STAT3-GSDMD-CASP4/5 pathway, collectively participate in the process of cell death. These pathways have an impact on the differentiation and proliferation of keratinocytes, and the pharmaceutical and herbal components targeting cell death provide new therapeutic solutions for treating psoriasis.

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国家自然科学基金资助项目（82074435）；2022年青年岐黄学者培养项目