Integrative Transcriptomic and Single-Cell Analysis Reveals the Role of Autophagy-Related Genes in Psoriasis Pathogenesis

Purpose: Psoriasis is a chronic inflammatory skin disease that is characterized by abnormal keratinocyte proliferation and differentiation. This study aimed to explore potential regulatory mechanisms and key genes related to autophagy in the pathogenesis of psoriasis. Patients and Methods: We performed pseudotime trajectory analysis and cell communication analysis on psoriasis and normal samples from single-cell RNA sequencing (scRNA-seq) data. Autophagy-related genes identified from scRNA-seq data were intersected with differentially expressed genes derived from the mRNA sequencing data. Protein-protein interaction (PPI) analysis was subsequently applied to identify candidate hub genes. Finally, the expression of these hub genes was validated in clinical cohorts and mouse models, thereby confirming the general applicability of hub genes in a larger patient cohort. Results: AUCell analysis revealed a predominant enrichment of autophagically active cells within the keratinocyte population. Along the keratinocyte differentiation trajectory, both the Renin angiotensin system (RAS) and NOD-like receptor signaling pathways were downregulated. Cell communication analysis revealed enhanced HLA-E-CD94/NKG2A inhibitory signals and weakened KLRK1 activating signals in the psoriatic microenvironment. These alterations are closely associated with mTORC1 hyperactivation-induced autophagy deficiency, which collectively impairs NK cell-mediated immune surveillance. In the imiquimod-induced model, three of the seven candidate hub genes (PKP3, SPRR2B, and KRT6B) were significantly upregulated compared with the controls. Subsequent sequencing and RT-qPCR analyses in the clinical cohort consistently demonstrated the upregulation of PKP3, SPRR2B, and KRT6B, supporting their roles as autophagy-related genes that mediate autophagic processes in psoriasis. Conclusion: These findings elucidate the potential mechanisms of autophagy-related genes in keratinocyte dysfunction and inflammatory progression in psoriasis, and may provide potential therapeutic targets against autophagy modulation.