GM2A links keratinocyte metabolism to inflammation in psoriasis: Integrated transcriptomic and functional analyses.

Psoriasis is a chronic inflammatory dermatosis driven by abnormal keratinocyte proliferation and extensive immune cell infiltration. Emerging evidence links its pathogenesis to lipid metabolic dysregulation, yet the specific molecules bridging lipid remodeling to immune activation remain largely unknown. In this study, we integrated transcriptomic datasets through weighted gene co-expression network analysis (WGCNA), differential expression analysis, and ensemble machine learning (random forest [RF] and support vector machine recursive feature elimination [SVM-RFE]), identifying ganglioside GM2 activator (GM2A) as a top lipid metabolism-related hub gene. Multi-cohort validation confirmed its robust upregulation in psoriatic lesions and its responsiveness to anti-psoriatic therapies. Furthermore, GM2A expression positively correlated with PASI scores and demonstrated strong diagnostic power in a nomogram-based model, reinforcing its candidacy as a diagnostic biomarker. Single-cell transcriptomic analysis revealed that GM2A is specifically elevated in spinous keratinocytes, where it drives ganglio-series glycosphingolipid reprogramming. Intercellular communication analysis demonstrated that spinous keratinocytes promote inflammatory infiltration primarily through the macrophage migration inhibitory factor (MIF)-CD74 signaling axis, targeting T cells and myeloid cells. In an imiquimod (IMQ)-induced psoriasis-like mouse model, GM2A was significantly upregulated and predominantly localized to the thickened spinous layer, accompanied by elevated levels of inflammatory cytokines. In M5-induced HaCaT cells, GM2A knockdown reduced the mRNA levels of IL-17 A, TNF, IL-6, and IL-1β, attenuated p65 phosphorylation, and decreased MIF release into the supernatant. Additionally, molecular docking identified cyclosporine A as a potential direct binder of GM2A with high affinity. Collectively, our study delineates a novel GM2A-driven metabolic-immune axis in psoriasis, positioning GM2A as a potential diagnostic biomarker and therapeutic target.