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

IF 3.1 4区医学 Q3 IMMUNOLOGY

Immunologic Research Pub Date : 2026-05-01 DOI:10.1007/s12026-026-09777-z

Qiu-Ju Wei, Jia-Rong Lu, Wan-Yan Xiang, Hai-Qi Liang, Si-Qi Zhang, Si-Yu Huang, Jun-Wen Peng, Ze-Feng Zhou, Qiu-Ju Li, Wen-Jun Zheng

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引用次数: 0

Abstract

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.

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皮肤成纤维细胞中的ANKFN1可能调节肥大细胞活性，并与特应性皮炎的杜匹单抗反应相关。

背景：特应性皮炎（AD）是一种常见的慢性炎症性皮肤病。Dupilumab是一种新的靶向药物，用于治疗中度至重度AD。然而，一些AD患者对dupilumab治疗反应不佳。目的：本研究旨在探讨ANKFN1在AD患者dupilumab耐药发展中的潜在作用和机制。方法：本研究对大量RNA、单细胞RNA （scRNA-seq）和空间转录组测序数据进行了综合分析。对54例接受dupilumab治疗的AD患者进行了前瞻性队列分析。基于SCORAD评分，我们测量了AD患者是否对16周的dupilumab治疗有反应。通过分析治疗前反应组和耐药组之间的差异表达基因，鉴定出耐药相关基因，并在独立数据集中进行外部验证。随后，利用生物学功能富集分析、免疫细胞评估、scRNA-seq分析和空间转录组学研究ANKFN1的生物学功能、细胞定位及其与免疫微环境的关联。此外，我们构建了ceRNA调控网络。结果：共鉴定出ANKFN1、HTR3A、HLA-DQA1、ALOX15B 4个关键基因，其中ANKFN1预测效果最强（AUC = 0.938），且在耐药组中表达显著上调，验证队列证实了这一发现。ANKFN1的高表达与静止肥大细胞浸润水平呈正相关，与免疫刺激因子、趋化因子和IL-4/IL-13通路受体（IL4R、IL13RA1、IL13RA2）呈负相关，提示其与免疫抑制微环境有关。scRNA-seq分析显示ANKFN1在成纤维细胞中特异性过表达，特别是在COL6A5 +成纤维细胞亚群中。空间转录组学分析进一步证实了这一发现。ceRNA网络提示ANKFN1可能受lncRNA NEAT1/miR-224轴和转录因子AR和GRHL2的调控。结论：ANKFN1可能与杜匹单抗无应答相关，值得进一步验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunologic Research 医学-免疫学

CiteScore

6.90

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.