ANKFN1 in skin fibroblasts may modulate mast cell activity and is associated with dupilumab response in atopic dermatitis.

BACKGROUND

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease. Dupilumab is a new targeted drug used to treat moderate to severe AD. However, some patients with AD exhibit poor response to dupilumab treatment.

OBJECTIVE

This study aims to investigate the potential role and mechanisms of ANKFN1 in the development of resistance to dupilumab in AD.

METHODS

This study conducted a comprehensive analysis of bulk RNA, single-cell RNA (scRNA-seq), and spatial transcriptome sequencing data. A prospective cohort of 54 AD patients treated with dupilumab was analyzed. Based on the SCORAD score, we measured whether the AD patients responded to 16 weeks of dupilumab treatment. By analyzing differentially expressed genes between the pre-treatment response group and the resistant group, drug resistance-associated genes were identified and externally validated in an independent dataset. Subsequently, biological function enrichment analysis, immune cells assessment, scRNA-seq analysis, and spatial transcriptomics were employed to investigate ANKFN1's biological functions, cellular localization, and association with the immune microenvironment. Additionally, we constructed a ceRNA regulatory network.

RESULTS

Four key genes ANKFN1, HTR3A, HLA-DQA1, and ALOX15B were identified, with ANKFN1 exhibiting the strongest predictive efficacy (AUC = 0.938) and showing significantly upregulated expression in the resistant group, a finding confirmed in the validation cohort. High ANKFN1 expression positively correlated with resting mast cell infiltration levels and negatively correlated with immune stimulatory factors, chemokines, and IL-4/IL-13 pathway receptors (IL4R, IL13RA1, IL13RA2), suggesting its association with an immunosuppressive microenvironment. scRNA-seq analysis revealed ANKFN1 was specifically overexpressed in fibroblasts, particularly within the COL6A5⁺ fibroblast subpopulation. Spatial transcriptomics analysis further validated this finding. The ceRNA network suggested ANKFN1 may be regulated by the lncRNA NEAT1/miR-224 axis and transcription factors AR and GRHL2.

CONCLUSION

ANKFN1 may be associated with dupilumab non-response and warrants further validation.