Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease among neonates, with increasing morbidity and mortality. This study aims to investigate the effect and mechanism of lysine demethylase 3A (KDM3A) on hyperoxia-induced BPD. Hyperoxia-induced BPD mouse and alveolar epithelial cell models were constructed. The effects of hyperoxia on lung development were evaluated by histological and morphological analysis. The levels of KDM3A, E26 transformation specific-1 (ETS1), H3 lysine 9 dimethylation (H3K9me2), and endoplasmic reticulum (ER) stress-related indexes were quantified by RT-qPCR, Western blot, and IF staining. Cell apoptosis was assessed by flow cytometry and TUNEL staining. Transfection of oe-ETS1, oe-KDM3A, and sh-ETS1 was applied in hyperoxia-induced alveolar epithelial cells to explore the mechanism of the KDM3A/ETS1 axis in hyperoxia-induced apoptosis. KDM3A inhibitor IOX1 was applied to validate the in vivo effect of KDM3A in hyperoxia-induced BPD mice. The results displayed that hyperoxia-induced BPD mice showed reduced body weight, severe destruction of alveolar structure, decreased radial alveolar count (RAC), and increased mean linear intercept (MLI) and mean alveolar diameter (MAD). Further, hyperoxia induction down-regulated ETS1 expression, raised ER stress levels, and increased apoptosis rate in BPD mice and alveolar epithelial cells. However, transfection of oe-ETS1 improved the above changes in hyperoxia-induced alveolar epithelial cells. Moreover, transfection of oe-KDM3A up-regulated ETS1 expression, down-regulated H3K9me2 expression, inhibited ER stress, and reduced apoptosis rate in hyperoxia-induced alveolar epithelial cells. In addition, transfection of sh-ETS1 reversed the inhibitory effect of KDM3A on hyperoxia-induced apoptosis by regulating ER stress. In vivo experiments, KDM3A inhibitor IOX1 intervention further aggravated BPD in newborn mice. In a word, KDM3A alleviated hyperoxia-induced BPD in mice by promoting ETS1 expression.

支气管肺发育不良（BPD）是新生儿中最常见的慢性肺部疾病，其发病率和死亡率不断增加。本研究旨在探讨赖氨酸脱甲基酶3A（KDM3A）对高氧诱导的BPD的作用及其机制。构建高氧诱导的 BPD 小鼠和肺泡上皮细胞模型。通过组织学和形态学分析评估高氧对肺发育的影响。通过RT-qPCR、Western blot和IF染色对KDM3A、E26转化特异性1（ETS1）、H3赖氨酸9二甲基化（H3K9me2）和内质网（ER）应激相关指标的水平进行定量。通过流式细胞术和TUNEL染色评估细胞凋亡。将oe-ETS1、oe-KDM3A和sh-ETS1转染高氧诱导的肺泡上皮细胞，探讨KDM3A/ETS1轴在高氧诱导的细胞凋亡中的机制。 KDM3A 抑制剂 IOX1 用于验证体内作用。结果显示，高氧诱导的BPD小鼠体重减轻，肺泡结构严重破坏，径向肺泡计数（RAC）减少，平均线性截距（MLI）和平均肺泡直径（MAD）增加。此外，高氧诱导下调 ETS1 表达，提高 ER 应激水平，并增加 BPD 小鼠和肺泡上皮细胞的凋亡率。然而，转染oe-ETS1改善了高氧诱导的肺泡上皮细胞的上述变化。此外，转染oe-KDM3A上调ETS1表达，下调H3K9me2表达，抑制ER应激，并降低高氧诱导的肺泡上皮细胞的凋亡率。此外，转染sh-ETS1通过调节ER应激逆转了KDM3A对高氧诱导的细胞凋亡的抑制作用。体内实验中，KDM3A抑制剂IOX1干预进一步加重了新生小鼠的BPD。总之，KDM3A 通过促进 ETS1 表达来减轻高氧诱导的小鼠 BPD。