<p>Generalized pustular psoriasis (GPP) is a rare and severe subtype of psoriasis, characterized by sterile pustules on the skin surface. Acitretin is currently one of the first-line treatments for GPP, while glucocorticoids are commonly used in patients with hyperpyrexia. However, the pathogenesis of GPP and the mechanisms of these drugs need to be further clarified. The clinical characteristics of GPP before and after treatment were collected and compared using student t tests or paired Wilcoxon tests. We analyzed the transcriptomic features of GPP using publicly available sequencing data. Subsequently, RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 29 GPP patients before and after treatment was conducted. The patients were divided into one group treated with acitretin alone (<i>n</i> = 25) and the other group treated with a combination of glucocorticoids (<i>n</i> = 4). Potential related genes were further validated using qRT-PCR in additional 17 patients. We observed that inflammatory signaling pathways were significantly upregulated in GPP and decreased after treatment, consistent with the reductions in inflammatory markers such as PGA scores, C-reactive protein (CRP) and neutrophil counts following treatment. Specifically, the expressions of several critical inflammation-related genes, such as CD14, CTSL, CEBPD, and IL1B, significantly decreased after treatment. Besides, compared to monotherapy with acitretin, the combination of acitretin with glucocorticoids can significantly reduce the expression of genes related to immune cell chemotaxis and activation. Acitretin can significantly reduce the inflammatory response of GPP patients. Combined use of glucocorticoids further reduces the expression of genes related to immune cell chemotaxis and activation. Key genes from these pathways are potential targets for developing novel treatment of GPP.</p>