Integrated transcriptomic and tissue-validation analyses identify palmitoylation-associated biomarkers linked to sphingolipid metabolism and immune remodeling in psoriasis.

BACKGROUND

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by epidermal dysfunction, aberrant keratinocyte activation, and complex immune remodeling. Although lipid dysregulation has increasingly been implicated in psoriasis, the role of palmitoylation-associated genes in cutaneous inflammation remains insufficiently defined.

METHODS

We integrated bulk transcriptomic datasets (GSE14905, GSE13355, and GSE121212) and a single-cell RNA-sequencing dataset (GSE151177) to identify palmitoylation-associated biomarkers in psoriasis. Weighted gene co-expression network analysis, differential expression analysis, and machine-learning algorithms including LASSO and SVM-RFE were applied to screen hub genes. Functional enrichment, immune microenvironment analysis, regulatory-network construction, and candidate-drug prediction were subsequently performed. In addition, RT-qPCR was used to validate the expression of candidate genes in psoriatic lesional skin and healthy control skin.

RESULTS

We identified 209 palmitoylation-associated differentially expressed genes and screened five candidate hub genes: CERK, SPTSSA, TNFSF10, CTNS, and HSD17B10. External validation supported the relative robustness of SPTSSA, TNFSF10, CTNS, and HSD17B10, whereas CERK remained a biologically relevant mechanistic candidate. A four-gene score derived from SPTSSA, TNFSF10, CTNS, and HSD17B10 defined a high-score state enriched in inflammatory, proliferative, and metabolic-stress pathways, including interferon responses, IL-6-JAK-STAT3 signaling, TNF signaling via NF-κB, complement, and inflammatory response. Immune deconvolution further revealed increased macrophage and activated dendritic-cell infiltration together with coordinated upregulation of multiple immune checkpoint molecules. Single-cell and correlation analyses suggested that SPTSSA showed relatively stronger expression in basal cells and keratinocytes, supporting a closer association with epidermal programs. CTNS also exhibited a mainly epidermal distribution, particularly in keratinocytes, whereas TNFSF10 displayed a more immune-related pattern and HSD17B10 showed a broader immune-metabolic distribution across multiple cell populations. RT-qPCR further supported the lesional upregulation of SPTSSA and HSD17B10, while CERK showed an opposite tissue-level trend and was therefore retained as a mechanistically informative candidate.

CONCLUSION

This study identifies a palmitoylation-associated molecular signature related with sphingolipid metabolism, keratinocyte activation, and immune remodeling in psoriasis. These findings not only provide candidate biomarkers for disease stratification, but also highlight potentially druggable pathways and therapeutic targets for future translational investigation.