现代预防医学

Gene name		Primer sequence（5’-3’）
Hsa-miR205	Forward	TCCTTCATTCCACCGGAGTCTG
	Reverse	加尾法通用引物R
Hsa-miR652	Forward	AATGGCGCCACTAGGGTTGT
	Reverse	加尾法通用引物R
U6	Forward	CTCGCTTCGGCAGCACA
	Reverse	AACGCTTCACGAATTTGCGT
Human GAPDH	Forward	GGGGTCGTTGATGGCAACA
	Reverse	AGGTCGGTGTGAACGGATTTG
Human COL1A1	Forward	GTGCGATGACGTGATCTGTGA
	Reverse	CGGTGGTTTCTTGGTCGGT
Human Vimentin	Forward	GGCTCAGATTCAGGAACAGC
	Reverse	GCTTCAACGGCAAAGTTCTC
Human Ecadherin	Forward	CAGAAAGTTTTCCACCAAAG
	Reverse	AAATGTGAGCAATTVTGCTT
Human TGFβ	Forward	TGTTGGTACCCAAGGAAAGC
	Reverse	CACTCTGTGGTTTGGAGCAA
Human β-Catenin	Forward	CATCTACACAGTTTGATGCTGC
	Reverse	GCAGTTTTGTCAGTTCAGGGA
Mouse Col1a1	Forward	CGCAAAGAGTCTACATGTCTAG
	Reverse	CATTGTGTATGCAGCTGACTTC
Mouse Vimentin	Forward	GGAATGCAGCCGTGGAACTT
	Reverse	TTGCAGCCTGGTGGGATCTT
Mouse αSMA	Forward	GGACGTACAACTGGTATTGTGC
	Reverse	TCGGCAGTAGTCACGAAGGA
Mouse Gapdh	Forward	AGGTCGGTGTGAACGGATTTG
	Reverse	TGTAGACCATGTAGTTGAGGTCA

Gene name		Primer sequence（5’-3’）
Hsa-miR205	Forward	TCCTTCATTCCACCGGAGTCTG
	Reverse	加尾法通用引物R
Hsa-miR652	Forward	AATGGCGCCACTAGGGTTGT
	Reverse	加尾法通用引物R
U6	Forward	CTCGCTTCGGCAGCACA
	Reverse	AACGCTTCACGAATTTGCGT
Human GAPDH	Forward	GGGGTCGTTGATGGCAACA
	Reverse	AGGTCGGTGTGAACGGATTTG
Human COL1A1	Forward	GTGCGATGACGTGATCTGTGA
	Reverse	CGGTGGTTTCTTGGTCGGT
Human Vimentin	Forward	GGCTCAGATTCAGGAACAGC
	Reverse	GCTTCAACGGCAAAGTTCTC
Human Ecadherin	Forward	CAGAAAGTTTTCCACCAAAG
	Reverse	AAATGTGAGCAATTVTGCTT
Human TGFβ	Forward	TGTTGGTACCCAAGGAAAGC
	Reverse	CACTCTGTGGTTTGGAGCAA
Human β-Catenin	Forward	CATCTACACAGTTTGATGCTGC
	Reverse	GCAGTTTTGTCAGTTCAGGGA
Mouse Col1a1	Forward	CGCAAAGAGTCTACATGTCTAG
	Reverse	CATTGTGTATGCAGCTGACTTC
Mouse Vimentin	Forward	GGAATGCAGCCGTGGAACTT
	Reverse	TTGCAGCCTGGTGGGATCTT
Mouse αSMA	Forward	GGACGTACAACTGGTATTGTGC
	Reverse	TCGGCAGTAGTCACGAAGGA
Mouse Gapdh	Forward	AGGTCGGTGTGAACGGATTTG
	Reverse	TGTAGACCATGTAGTTGAGGTCA

miR-205通过NKD1-Wnt-EMT通路调节特发性肺纤维化

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姜逸林 , 陈天源 , 李泽艳 , 鲍其雪 , 姚于勤 , 伍东升 , 彭莉君 , 张凌

现代预防医学 | 实验技术及其应用 2026,53(14): 2648-2655

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现代预防医学 |实验技术及其应用 2026 , 53 (14) : 2648 -2655

miR-205通过NKD1-Wnt-EMT通路调节特发性肺纤维化

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姜逸林, 陈天源, 李泽艳, 鲍其雪, 姚于勤, 伍东升, 彭莉君, 张凌

作者信息

四川大学华西公共卫生学院/华西第四医院卫生毒理学与病理学系，四川省教育厅分子毒理学重点实验室，四川成都 610041

通讯作者:

张凌，E-mail：zhangling83@scu.edu.cn

作者简介:

姜逸林（2000—），男，硕士在读，研究方向：卫生毒理学

miR-205 regulates idiopathic pulmonary fibrosis through NKD1-Wnt-EMT pathway

Yi-lin JIANG, Tian-yuan CHEN, Ze-yan LI, Qi-xue BAO, Yu-qin YAO, Dong-sheng WU, Li-jun PENG, Lin ZHANG

Affiliations

Department of Health Toxicology and Pathology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Key Laboratory of Molecular Toxicology of Sichuan Provincial Department of Education, Chengdu, Sichuan 610041, China

出版时间: 2026-07-25 doi: 10.20043/j.cnki.MPM.202604070

文章导航

摘要

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目的

筛选影响特发性肺纤维化的关键miRNA，探究其具体机制与信号通路。

方法与结果

通过分析IPF患者肺组织中的miRNA，发现miR-205显著上调（logFC=1.91，adj. P. Value<0.05）。体外实验证实，miR-205直接靶向并抑制NKD1的表达，进而调控Wnt/β-Catenin信号通路，影响EMT过程，从而调节细胞迁移及纤维化进程。制备包含miR-205抑制剂的脂质纳米颗粒，并在小鼠肺纤维化模型中评估其治疗效果。经气管滴注给药后，i205-LNP显著上调NKD1的表达，与造模组相比提高约4.05倍（P<0.05），并降低肺组织中纤维化相关标志物α-sma（约15%，P<0.001）及Col1a1（约25%，P<0.001）的表达水平，小鼠肺部炎症与纤维化得到缓解，体重下降减轻，生存率提高。

结论

miR-205抑制靶基因NKD1的表达，通过Wnt-EMT信号通路促进特发性肺纤维化的发生。

关键词

特发性肺纤维化 / miR-205 / NKD1 / Wnt/β-Catenin / 上皮间质转化

Abstract

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Objective

To identify key microRNAs involved in idiopathic pulmonary fibrosis (IPF) and investigate the underlying mechanisms.

Methods & Results

Analysis of miRNA expression in lung tissues from IPF patients revealed a significant upregulation of miR-205 (logFC=1.91, adj. P. Value<0.05). In vitro experiments confirmed that miR-205 directly targets and suppresses NKD1 expression, thereby modulating the Wnt/β-Catenin signaling pathway and influencing epithelial-mesenchymal transition (EMT), which in turn regulates cell migration and fibrotic progression. Lipid nanoparticles encapsulating a miR-205 inhibitor (i205-LNP) were formulated and evaluated for therapeutic efficacy in a mouse model of pulmonary fibrosis. Following intratracheal administration, i205-LNP significantly upregulated NKD1 expression by approximately 4.05-fold compared to the model group (P<0.05) and reduced the levels of fibrosis-related markers, including α-SMA (approximately 15%, P<0.001), and Col1a1 (approximately 25%, P<0.001) in lung tissues. Consequently, pulmonary inflammation and fibrosis were alleviated, accompanied by attenuated body weight loss and improved survival rates in treated mice.

Conclusion

miR-205 promotes the pathogenesis of idiopathic pulmonary fibrosis by suppressing its target gene NKD1 via the Wnt-EMT signaling pathway.

Key words

Idiopathic pulmonary fibrosis / miR-205 / NKD1 / Wnt/β-Catenin / Epithelial-mesenchymal transition

引用本文

姜逸林, 陈天源, 李泽艳, 鲍其雪, 姚于勤, 伍东升, 彭莉君, 张凌. miR-205通过NKD1-Wnt-EMT通路调节特发性肺纤维化. 现代预防医学, 2026 , 53 (14) : 2648 -2655 . DOI: 10.20043/j.cnki.MPM.202604070

Yi-lin JIANG, Tian-yuan CHEN, Ze-yan LI, Qi-xue BAO, Yu-qin YAO, Dong-sheng WU, Li-jun PENG, Lin ZHANG. miR-205 regulates idiopathic pulmonary fibrosis through NKD1-Wnt-EMT pathway[J]. Modern Preventive Medicine, 2026 , 53 (14) : 2648 -2655 . DOI: 10.20043/j.cnki.MPM.202604070

正文

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特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）是一种慢性、进行性、纤维化性间质性肺疾病，组织学和（或）胸部HRCT特征性表现为普通型间质性肺炎（UIP）。IPF病情凶险，确诊后的中位生存时间为3～5年^[1]。目前有两种治疗IPF药物，吡非尼酮和尼达尼布^[2]。虽然这两种药物都能减缓疾病的进展，但它们并不能治愈IPF。目前迫切的需要研究新的疗法来提高患者的生存率。

全球IPF的患病率和年发病率分别是（3～45）/10万人口和（1～13）/10万人口^[3]。随着全球人口老龄化及潜在危险因素的增多，IPF将带来更加沉重的疾病负担。IPF的病因不明确，诊断时间通常为56～69岁，且发病率及患病率有随年龄升高而增高的趋势，可能反应衰老相关的过程^[4-5]。衰老是一个动态的过程^[6]，其定义为机体各系统随时间推移而出现的功能衰退^[7]。衰老涉及多种细胞及分子水平的改变。其中，表观遗传学的改变是衰老的重要细胞机制之一^[8-9]。

MicroRNAs（miRNAs）是长度在19～25 nt的内源性非编码RNA（non-coding RNA，ncRNA），是调控蛋白质生物合成的一类重要的ncRNA^[10]。miRNA通过与蛋白质结合形成复合物，即miRNA诱导的沉默复合物（miRISC），通过复合物中的蛋白成分对翻译过程产生抑制作用^[11]。miRNA是影响IPF发生的重要因素，研究表明，let-7d、miR-142-3p、miR-15a等多种miRNA通过调节上皮-间质转化（EMT）过程参与IPF的形成^[12-14]。值得关注的是，Wnt/β-Catenin信号通路在IPF病理过程中呈异常激活状态，并与EMT、炎症反应及氧化应激等病理过程密切相关^[15]。最近的研究发现，多种miRNA可通过直接靶向Wnt/β-Catenin通路的关键因子参与纤维化调控。Liu等研究表明，miR-27a-3p通过靶向Wnt3a的3’-非翻译区，抑制Wnt3a/β-Catenin信号通路活性，从而减少肺成纤维细胞I型和III型胶原合成^[16]。Yu等则揭示了miR-29b-TRIOBP-TRIO-β-Catenin调控轴在IPF疾病发展过程的重要作用^[17]。此外，外泌体介导的miRNA转运途径进一步丰富了miRNA调控Wnt/β-catenin/EMT轴的机制网络。研究表明，miR-4687-5p通过靶向β-Catenin抑制其核转位，阻断Wnt/β-catenin通路对EMT的驱动作用，从而发挥抗纤维化的作用^[18]。然而，目前关于miRNA通过Wnt/β-Catenin-EMT通路调节特发性肺纤维的研究较少，miRNA参与纤维化信号传导通路也有待进一步验证与探索。

本研究通过生物信息分析、肺纤维化动物及细胞模型的构建，分析miRNA在正常与疾病模型之间表达的差异，探究其对肺纤维化的影响及其潜在的机制。研究将肺纤维发生的过程与相关的组织病理学机制提供思路。

1　材料与方法

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1.1　实验动物

健康雄性SPF级C57BL6/J小鼠（6～8周龄，18～22 g）购自北京维通利华。于四川大学华西药学院SPF级实验动物中心适应性饲养1周，自由饮水摄食，温度20～24℃、湿度40%～60%、12 h明暗交替。所有实验操作均通过四川大学医学伦理委员会批准（Gwll2023055）。

1.2　试剂

盐酸博来霉素（67763-87-5）购自KKL公司；1，2-二油醇-3-二甲基氨基-丙烷（104162-47-2）、1，2-二油酰基-sn-丙三基-3-磷脂酰乙醇胺（4004-05-1）、胆固醇（57-88-5）购自阿拉丁试剂公司；兔抗Collagen I多抗（ab316222）、兔抗α-SMA单抗（ab124964）、鼠抗GAPDH单抗（ab8245）购自Abcam公司；兔抗NKD1多抗（HA500419）、山羊抗兔HRP标记二抗（HA1001）、山羊抗鼠HRP标记二抗（HA1006）购自杭州华安生物有限公司；细胞总RNA提取试剂盒（RE-03113）、动物组织总RNA提取试剂盒（RE-03014）购自福际生物技术有限公司；RNA逆转录试剂（RK20429）购自武汉爱博泰克生物科技有限公司；实时荧光定量PCR试剂盒（Q712-01）购自南京诺唯赞生物科技股份有限公司；has-miR-205-5p inhibitor（HY-RI00421）购自MCE公司；Human/Mouse TGF-β检测试剂盒（EK981）、Mouse TNF-a检测试剂盒（EK282）、Mouse IL-6检测试剂盒（EK206）购自联科生物；RNA转染试剂（E607402）购自生工公司。

1.3　仪器

Olympus全自动病理切片扫描机（奥林巴斯）；酶标仪（赛默飞世尔科技公司）；QuantStudio 3实时荧光定量PCR系统（赛默飞世尔科技公司）；iBright^TM CL750成像系统（赛默飞世尔科技公司）。

1.4　实验方法

1.4.1　小鼠肺纤维化模型构建

小鼠随机分为3组（每组20只）：生理盐水对照组、博来霉素模型组、博来霉素+iLNP-205治疗组。腹腔注射2%戊巴比妥钠（50 mg/kg）麻醉后，经非暴露气管滴注博来霉素（3 mg/ml，50 μl）或等体积生理盐水。治疗组于第1、7、14、21天经气管滴注i205-LNP（50 μl，含8 μg miR-205反义链）。第28天处死取肺：肺尖固定于4%多聚甲醛，其余组织液氮速冻后-80 ℃保存。

1.4.2　组织切片与染色

肺组织经4%多聚甲醛固定、脱水、石蜡包埋后，以4 μm厚度切片，贴片后烘干。使用苏木精-伊红（HE）染色观察小鼠肺部炎性状况，使用Masson三色染色技术评估肺组织纤维化情况，采用Ⅰmage J对胶原纤维区域进行识别，评价胶原纤维蓝色区域占全肺染色比重。

1.4.3　细胞培养

A549细胞在含有10%胎牛血清的DMEM培养基中培养，细胞密度达到90%时消化，取5×10⁵个细胞接种于六孔板上。12 h贴壁后更换无血清DMEM培养基饥饿6 h，将RNA转染试剂与无血清培养基混合并加入相应miRNA inhibitor，转染6 h后，换液并进行后续操作。

1.4.4　RT-qPCR

细胞或组织用试剂盒提取总RNA，NanoDrop 2000检测纯度（A260/A280及A260/A230在1.8～2.1）。mRNA逆转录体系含ABScript III RT Mix 4 μl、gDNA Remover Mix 1 μl、总RNA 1 μg，RT反应程序设定为：37℃ 2 min，55℃ 15 min，85℃ 5 min。miRNA逆转录体系含miRNA P-RT Solution mix 10 μl、Enzyme mix 2 μl、总RNA 1 μg，反应程序设定为程序：37℃ 60 min，85℃ 5 min。qPCR反应条件为95℃ 5 min，95℃ 10 s，60℃ 10 s，72℃ 10 s，共40个循环；溶解曲线为95℃ 10 s，60℃ 60 s，95℃ 10 s。mRNA以GAPDH作为内参，miRNA以U6作为内参，使用2^-ΔΔCt法定量分析。引物序列详见表1，均购自生工公司。

1.4.5　Western blot

细胞或组织（约10 mg）用RIPA裂解液（含蛋白酶/磷酸酶抑制剂）提取蛋白，使用BCA法定量。样品与5×上样缓冲液混合后100℃加热5 min。SDS-PAGE（150 V，60 min）后湿转至PVDF膜（260 mA，60 min），封闭后一抗4℃孵育过夜，二抗室温孵育1 h，ECL显影，以GAPDH作为内参，使用Image J分析蛋白表达强度。

1.4.6　免疫荧光

细胞爬片经PBS预处理后接种细胞（1×10⁴/ml），干预后用4%多聚甲醛固定30 min，1% Triton X-100通透20 min，10%山羊血清封闭1 h，一抗4 ℃孵育过夜，荧光二抗室温避光孵育1 h，DAPI染核5 min，封片后荧光显微镜观察。

1.4.7　划痕实验

6孔板背面划线，接种细胞（5×10⁵/ml）。培养至90%融合，用200 μl枪头划痕，PBS洗涤去除脱落细胞。于0、6、12 h拍照，Image J测量划痕面积，细胞迁移能力通过伤口愈合百分比表示，计算公式如下：

1.4.8　细胞迁移实验

转染miR-205 inhibitor的细胞以无血清DMEM重悬，取200 μl（5×10⁴个）加入上室，下室加700 μl含10% FBS的DMEM。培养24 h后，擦除上室未迁移细胞，4%多聚甲醛固定，结晶紫染色，镜下随机5个视野计数。

1.4.9　统计分析

数据以

表示。使用GraphPad Prism 8.0软件进行单因素方差分析（LSD或Dunnett’s T3法）或非配对t检验。检验水准α=0.05。

2　结果

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2.1　IPF患者与对照组差异性miRNA生物信息学分析

本研究利用GEO公开数据集（GEO accession: GSE32538），通过生物信息学方法分析特发性肺纤维化（IPF）患者与对照人群之间miRNA表达的差异。计算基因表达折叠变化（logFC），方法如前所述^[16]。对每个miRNA的表达拟合线性模型，采用经验贝叶斯方法进行残差分析，获得t统计量及校正后P值（adj. P. Val）。以logFC>1.2且adj. P. Val<0.05为阈值，绘制火山图和热图（图1A、B）。与对照组相比，IPF患者miR-205表达升高，差异具有统计学意义。

采用Funrich软件^[19]分析差异表达miRNA可能参与的通路及机制。如图1C所示，IPF与对照组差异表达miRNA潜在涉及的生物学通路包括：VEGF-VEGFR通路（34.1%，P=0.002）、IFN-γ通路（33.6%，P=0.003）。分子功能（MF）网络分析显示，差异表达miRNA主要作用于转录因子活性、泛素特异性蛋白酶活性调控及蛋白结合调控。细胞组分（CC）网络分析表明，差异性miRNA主要在细胞质和细胞核中发挥作用（图1D、E）。

2.2　miR-205对特发性肺纤维化的影响

本研究进一步在体外模型中探究miR-205对特发性肺纤维的影响及机制。采用博来霉素刺激A549细胞建立纤维化模型，通过RT-qPCR和Western blot确定诱导纤维化最佳浓度。100 μM博来霉素处理24小时后，纤维化相关基因及蛋白（COL1A1、Vimentin和α-SMA）表达显著升高，因此选定该条件作为造模方案（图2A、B）。采用AF488标记miR-205 inhibitor转染并通过共聚焦显微镜观测，确定miR-205抑制剂的最佳转染浓度为20 nM（图2C）。RT-qPCR分析证明miR-205被浓度依赖性地沉默（最高剂量下敲低约60%），且无脱靶效应（图2D）。α-SMA免疫荧光评估显示，博来霉素可诱导A549细胞发生纤维化，而干扰miR-205可明显减弱这一效应（图2E）。这些结果表明，在体外模型中抑制miR-205具有一定的抗纤维化作用。

2.3　miR-205通过NKD1-Wnt-EMT通路调节特发性肺纤维化

既往研究表明，miRNA通过与靶基因3’-非翻译区（3’-UTR）结合发挥其生物学功能^[20]。因此，鉴定miR-205的潜在靶点对于阐明其在IPF中的作用至关重要。利用TargetScan预测miR-205的潜在靶基因。分析显示，在NKD1（naked cuticle homolog 1）mRNA的3’-UTR内存在7个miR-205的潜在结合位点，提示NKD1是miR-205的潜在靶基因（图3A）。

为验证这一靶向关系，本研究进行了双荧光素酶报告基因检测。结果表明miR-205与NKD1 3’-UTR上的预测位点特异性结合发挥调控作用（图3B）。Western blot实验进一步在蛋白水平证实了这一调控关系。如图3C所示，博来霉素处理显著下调A549细胞中NKD1蛋白的表达。使用miR-205 inhibitor干扰后，NKD1表达呈剂量依赖性恢复。

之前的研究表明，NKD1是Wnt信号通路的负调控因子^[21]，而Wnt信号通路失调可通过驱动上皮-间充质转化（EMT）过程促进肺纤维化^[22]，本研究推测抑制miR-205可能通过上调NKD1抑制Wnt-EMT信号通路。为验证这一假设，本研究检测A549细胞中相关基因的表达。结果发现，抑制miR-205可下调Wnt通路标志物β-Catenin的表达，并缓解了博来霉素诱导间质标志物Vimentin的过表达与上皮标志物E-cadherin的下调（图3D）。细胞形态学的变化进一步证明了miR-205对EMT过程的影响，划痕实验显示，博来霉素显著增强A549细胞的迁移能力，而干扰miR-205可有效抑制该效应（图3E）。同样，Transwell迁移实验表明，博来霉素诱导的细胞迁移可被miR-205抑制剂显著减弱（图3F）。综上所述，这些数据揭示了一条机制通路：抑制miR-205通过NKD1-Wnt-EMT通路减轻IPF。

2.4　干扰miR-205减轻博来霉素诱导小鼠肺纤维化

本研究在博来霉素诱导的IPF小鼠模型中评估了体内抑制miR-205的治疗效果。根据之前的研究^[23]，合成包含miR-205反义寡核苷酸的阳离子脂质纳米颗粒（i205-LNP），通过气管滴注实现对miR-205表达的敲低。对合成的i205-LNP进行表征，其平均流体动力学直径（Z-Average）为（255.9±6.8）nm，粒径分布窄且单分散性良好。Zeta电位为+39.7 mV，有利于细胞高效摄取^[24]。

经过一周的检疫和适应期后，根据体重将小鼠随机分为三组：对照组、博来霉素诱导的IPF模型组（BLM组）和i205-LNP治疗组。在第0天通过气管滴注博来霉素（3 mg/ml，50 μl）构建肺纤维化模型。根据之前的研究^[25]，在造模后第1天通过气管滴注i205-LNP（50 μl，含8 μg miR-205反义链）进行预防性治疗，之后在第7天、第14天，第21天同样操作给药进行治疗，造模后第28天处死小鼠收集组织进行后续分析，具体流程图见图4A。体重监测显示，与对照组相比，BLM小鼠体重显著下降；而i205-LNP可有效改善这趋势（图4B）。与BLM组相比，i205-LNP治疗组小鼠死亡率显著降低（图4C）。治疗后第28天，处死小鼠并收集组织。对小鼠肺组织称重发现，BLM组肺湿重较对照组显著增加；而i205-LNP治疗组的肺重/体重比呈现下降趋势，提示该干预具有潜在抗纤维化效应（图4D）。此外，经i205-LNP治疗后，IPF模型小鼠的炎症明显减轻。对促炎及促纤维化因子的分析显示，BLM组与治疗组之间TGF-β、TNF-α和IL-6水平存在显著差异（图4E）。此外，外周血细胞计数表明，抑制miR-205可有效减轻BLM造成的小鼠全身性炎症反应（图4F）。

本研究进一步评估了抑制miR-205对肺组织病理性重塑的影响。组织病理学染色显示，i205-LNP治疗后肺内纤维化区域减少（图5A, B）。通过羟脯氨酸法对肺组织中总胶原进行定量，得到了相互印证的结果（图5C）。采用Western blot进一步验证i205-LNP的治疗机制。抑制miR-205后，BLM小鼠肺组织中NKD1蛋白表达显著上调，同时伴随β-Catenin的抑制，进而减弱了BLM诱导的肺纤维化标志蛋白COL1A1的表达（图5D）。

此外，从小鼠肺组织中提取总RNA，通过RT-qPCR分析纤维化相关基因（Vimentin、α-sma、Col1a1）的表达。与BLM组相比，i205-LNP治疗组小鼠纤维化标志物的表达均显著下调（图5E）。综上所述，抑制miR-205通过发挥抗炎与抗纤维化的作用，显著减轻博来霉素诱导的小鼠肺纤维化。

3　讨论

收起

特发性肺纤维化（IPF）是一种慢性、进行性且致命的间质性肺病。其发病机制尚不完全明确，目前公认的核心机制包括上皮细胞损伤、异常修复、成纤维细胞灶的形成以及细胞外基质代谢失调^[26-27]。

近年来，表观遗传调控，尤其是微小RNA（miRNA）的作用，因其在体内功能的多样性而引起了广泛关注^[28]。miRNA是一类长约22个核苷酸的非编码RNA，主要通过结合靶mRNA的3’非翻译区，在转录后水平调控基因表达^[29-30]。一个miRNA可调控数百个不同的mRNA，形成复杂的调控网络，在细胞命运决定、个体发育及疾病发生发展中扮演关键角色^[31-32]。

通过整合生物信息学分析、动物模型验证和体外细胞实验，我们系统揭示了miR-205在IPF中的关键作用，并阐明其通过靶向NKD1调控Wnt/β-Catenin信号通路进而影响上皮-间充质转化过程的新机制。通过TargetScan预测及双荧光素酶报告基因实验，我们发现NKD1是miR-205的直接靶基因。NKD1是Wnt/β-Catenin通路的经典内源性负调控因子，通过促进β-Catenin降解来抑制该通路活性^[33-34]。虽然已知Wnt通路的异常激活是EMT及肺纤维化发病机制的关键驱动因素^[35-36]，但本研究首次将NKD1与肺纤维化相关联，也为纤维化研究提供了新的潜在蛋白靶点。此外，本研究的划痕实验和Transwell实验表明，抑制miR-205可有效减弱博来霉素诱导的A549细胞迁移和侵袭能力的增强，提示miR-205的促纤维化作用和其促进EMT相关。这与miR-205在多种癌症中高表达并促进EMT的现象一致^[37-38]。

随后，本研究通过气道给予LNP递送系统，在体内验证了miR-205的治疗潜力。该治疗系统简单有效，显示了miR-205以及在肺部疾病中的转化可能性。同时实验结果证明了miR-205在体内外均可一致性地调控其靶基因NKD1，揭示了NKD1-Wnt-EMT轴是肺纤维化的一个可行且关键的治疗靶点。

然而，本研究仍存在一些局限性。博来霉素诱导的小鼠模型虽然是研究IPF最广泛使用的模型之一，但它是一种急性损伤模型，其病理过程与人类IPF的慢性、进行性特征不同^[39-40]。此外，虽然博来霉素可造成肺上皮细胞损伤、成纤维细胞异常活化和上皮间质转化（EMT）等病理过程，反映从炎症到纤维化的疾病过程^[41]，但其诱导的肺纤维化在啮齿动物上存在着自限性与可逆性等局限^[42]。最后，尽管本研究已通过双荧光素酶报告基因实验初步证明miR-205对NKD1基因的靶向调控作用，但由于单个miRNA可以调控广泛的靶点，单个基因也可能受多个miRNA的调控^[43]，miR-205在肺纤维化环境中复杂的调控网络还有待深入探究，miR-205-NKD1调节通路也有待进一步的验证。这在一定程度上限制了结论的普适性。

基金

收起

国家自然科学基金联合项目(U23A20495)
国家重点研发计划(2023YFC2509300)

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2026年第53卷第14期

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doi: 10.20043/j.cnki.MPM.202604070

接收时间：2026-04-04
首发时间：2026-09-28
出版时间：2026-07-25

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收稿日期：2026-04-04

基金

国家自然科学基金联合项目(U23A20495)

国家重点研发计划(2023YFC2509300)

作者信息

四川大学华西公共卫生学院/华西第四医院卫生毒理学与病理学系，四川省教育厅分子毒理学重点实验室，四川成都 610041

通讯作者:

张凌，E-mail：zhangling83@scu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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