Integrated multi-omics identifies GZMA targeting NK cells as a novel therapeutic strategy for hidradenitis...

Hidradenitis suppurativa (HS) represents a prevalent inflammatory dermatosis that not only triggers persistent local inflammation but also imposes significant psychosocial burdens. Given that the pathogenesis of HS remains incompletely elucidated, there is an urgent need necessitating the development of precision intervention strategies grounded in patients' immune profiles.

To investigate the pathogenesis of hidradenitis suppurativa, we employed an integrative approach combining bulk transcriptomics, Mendelian randomization (MR), and single-cell transcriptomic profiling. Specifically, transcriptomic analysis utilized Weighted Gene Co-Expression Network Analysis(WGCNA) for co-expression network construction and Least Absolute Shrinkage and Selection Operator(LASSO) regression for feature selection. Mendelian randomization applied IVW, weighted median, simple mode, weighted mode, and Bayesian MR approaches to ensure robust causal inference, with mediation analysis identifying potential metabolites. Molecular docking simulations were conducted to validate drug candidates targeting core genes. For single-cell transcriptomic analysis, we leveraged Gene Expression Omnibus(GEO) datasets followed by dispersion reduction, clustering, and cell-cell communication analysis to elucidate underlying cellular mechanisms.

Our transcriptomic analysis identified Granzyme A(GZMA) as a central therapeutic target (Discovery cohort ROC: 0.945; Validation cohort ROC: 0.819). Furthermore, Mendelian randomization analysis indicated a heightened causal association between GZMA and HS risk: IVW (OR = 1.62, 95 %CI:1.24-2.11; p = 0.0003) and BWMR (OR = 1.62, 95 %CI:1.26-2.08; p = 0.0002). Critically,​mediation analysis established N-Acetylputrescine as a potential mediating metabolite. Shifting to the cellular level, single-cell sequencing revealed prominent GZMA expression specifically within NK cells. Analysis of cell-cell interactions revealed communication between NK cells and both T cells and B cells, and highlighted differences in the communication dynamics between GZMA-positive and GZMA-negative subpopulations.

Integrative analysis of transcriptomic, MR, and scRNA-seq data strongly implicates GZMA as a potential therapeutic target and highlights the crucial role of NK cells in HS pathogenesis. These findings provide novel insights into HS immunopathology and pave the way for targeted therapeutic development.