Shu Fu, Wang Yaping, Jiang Yiheng, Li Linglong, Mu Zengyi, Shi Lei, Gong Xiaobao, Zhang Baoshun, Zhang Feng, Mao Dehong
College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 400000, People's Republic of China.
College of Pharmaceutical Sciences, Southwest University, Chongqing, 400000, People's Republic of China.
J Inflamm Res. 2025 Jul 30;18:10235-10251. doi: 10.2147/JIR.S521536. eCollection 2025.
Type 2 inflammation and epithelial-mesenchymal transition (EMT) are critical components in the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS), yet their upstream regulatory mechanisms remain poorly understood. This study aimed to explore the regulatory role of miR-301b-3p in these mechanisms and evaluate its therapeutic potential.
High-throughput miRNA sequencing of human and mouse nasal mucosa tissues identified miR-301b-3p as a key candidate molecule. Mendelian randomization (MR) analysis confirmed its causal relationship with chronic rhinosinusitis (CRS). The role of miR-301b-3p and its target gene PIK3CB in ECRS was further investigated using bioinformatics analysis, dual-luciferase reporter assays, adeno-associated virus (AAV)-mediated modulation of miR-301b-3p expression, histological staining, and a range of molecular biology techniques to elucidate the underlying mechanisms. The role of PIK3CB was assessed using the PIK3CB inhibitor TGX-221.
hsa-miR-301b-3p was significantly downregulated in ECRS patient nasal mucosa (log2FC = -1.636, P = 0.010), and its expression level negatively correlated with disease severity; simultaneously, mmu-miR-301b-3p was significantly downregulated in the ECRS mouse model (log2FC = -2.256, P = 0.041). MR analysis demonstrated a causal relationship between reduced miR-301b levels and increased CRS risk (OR = 0.956; 95% CI, 0.918-0.996; P = 0.033). In vivo experiments revealed that miR-301b-3p knockdown led to PIK3CB upregulation and activation of the PI3K-AKT pathway, triggering type 2 inflammation and EMT. Conversely, overexpression of miR-301b-3p suppressed PIK3CB expression and mitigated these pathological changes. Notably, the PIK3CB inhibitor TGX-221 reversed PI3K-AKT hyperactivation induced by miR-301b-3p knockdown, alleviating type 2 inflammation and EMT.
miR-301b-3p regulates type 2 inflammation and EMT in ECRS by targeting PIK3CB and modulating the PI3K-AKT pathway, suggesting both miR-301b-3p and PIK3CB as promising therapeutic targets. Given the limited sample size of this study, we plan to expand our cohort and implement a longitudinal follow-up design to monitor dynamic changes in miR-301b-3p expression and their relationship to disease progression.
2型炎症和上皮-间质转化（EMT）是嗜酸性粒细胞性慢性鼻-鼻窦炎（ECRS）发病机制的关键组成部分，但其上游调控机制仍知之甚少。本研究旨在探讨miR-301b-3p在这些机制中的调控作用，并评估其治疗潜力。
对人和小鼠鼻黏膜组织进行高通量miRNA测序，确定miR-301b-3p为关键候选分子。孟德尔随机化（MR）分析证实了其与慢性鼻-鼻窦炎（CRS）的因果关系。使用生物信息学分析、双荧光素酶报告基因检测、腺相关病毒（AAV）介导的miR-301b-3p表达调控、组织学染色以及一系列分子生物学技术，进一步研究miR-301b-3p及其靶基因PIK3CB在ECRS中的作用，以阐明潜在机制。使用PIK3CB抑制剂TGX-221评估PIK3CB的作用。
hsa-miR-301b-3p在ECRS患者鼻黏膜中显著下调（log2FC = -1.636，P = 0.010），其表达水平与疾病严重程度呈负相关；同时，mmu-miR-301b-3p在ECRS小鼠模型中显著下调（log2FC = -2.256，P = 0.041）。MR分析表明miR-301b水平降低与CRS风险增加之间存在因果关系（OR = 0.956；95% CI，0.918 - 0.996；P = 0.033）。体内实验表明，miR-301b-3p敲低导致PIK3CB上调和PI3K-AKT通路激活，引发2型炎症和EMT。相反，miR-301b-3p过表达抑制PIK3CB表达并减轻这些病理变化。值得注意的是，PIK3CB抑制剂TGX-221逆转了miR-301b-3p敲低诱导的PI3K-AKT过度激活，减轻了2型炎症和EMT。
miR-301b-3p通过靶向PIK3CB并调节PI3K-AKT通路来调控ECRS中的2型炎症和EMT，提示miR-301b-3p和PIK3CB均为有前景的治疗靶点。鉴于本研究样本量有限，我们计划扩大队列并实施纵向随访设计，以监测miR-301b-3p表达的动态变化及其与疾病进展的关系。
