Abstract：
Chronic obstructive pulmonary disease (COPD) is potentially fatal, and as society ages, its effects on human health are predicted to deteriorate. The potential function of m6A modifications within COPD has become a hot topic recently. This study was conducted to clarify the function and related mechanisms of the m6A methylation transferase ZC3H13 in COPD. The expression of m6A-associated protease and ITGA6 in COPD tissues was assessed using GEO data, qRT-PCR, and western blot. COPD models in cells and mice were established through cigarette smoke extract (CSE) and smoke exposure. Inflammatory marker levels were measured by ELISA, apoptosis by flow cytometry, and mRNA stability with Actinomycin D assay. m6A modification levels were checked by MeRIP-PCR. HE and Masson staining evaluated lung pathology, and alveolar lavage fluid analysis included total cell count and Giemsa staining. ZC3H13 and METTL3 were differentially expressed m6A regulators in COPD, with ZC3H13 being more significantly upregulated. Further analysis revealed the ZC3H13 expression-related differentially expressed genes (DEGs) functions were enriched in the immunoinflammatory pathway, indicating ZC3H13\'s involvement in COPD pathogenesis through inflammation, and immune responses. Knockdown studies in cellular and mouse models demonstrated ZC3H13\'s role in exacerbating COPD symptoms, including inflammation, apoptosis, and EMT, and its suppression led to significant improvements. The identification of ITGA6 as a target gene further elucidated the mechanism, showing that ZC3H13 enhances ITGA6 expression and mRNA stability through m6A modification, influencing bronchial epithelial cell inflammation and fibrosis. In conclusion, targeting ZC3H13/ITGA6 could be an underlying therapeutic approach for treating COPD.
摘要：
慢性阻塞性肺疾病（COPD）可能是致命的，随着社会的老化，它对人类健康的影响预计会恶化。m6A修饰在COPD中的潜在功能已成为最近的热门话题。本研究旨在阐明m6A甲基化转移酶ZC3H13在COPD中的作用及相关机制。使用GEO数据评估COPD组织中m6A相关蛋白酶和ITGA6的表达，qRT-PCR,和westernblot.通过香烟烟雾提取物（CSE）和烟雾暴露在细胞和小鼠中建立COPD模型。通过ELISA测量炎症标志物水平，通过流式细胞术细胞凋亡，放线菌素D测定和mRNA稳定性。通过MeRIP-PCR检查m6A修饰水平。HE和Masson染色评估肺病理，肺泡灌洗液分析包括总细胞计数和Giemsa染色。ZC3H13和METTL3是COPD中差异表达的m6A调节因子，ZC3H13上调更显著。进一步的分析显示，ZC3H13表达相关的差异表达基因（DEGs）功能在免疫炎症途径中富集，表明ZC3H13通过炎症参与COPD的发病机制，和免疫反应。细胞和小鼠模型的击倒研究表明ZC3H13在加重COPD症状中的作用，包括炎症,凋亡，和EMT,它的抑制导致了显著的改善。ITGA6作为靶基因的鉴定进一步阐明了其作用机制,显示ZC3H13通过m6A修饰增强ITGA6表达和mRNA稳定性，影响支气管上皮细胞炎症和纤维化。总之,靶向ZC3H13/ITGA6可能是治疗COPD的潜在治疗方法.
