Liu Xuanqi, Zhang Linlin, Li Liyang, Hou Jiayun, Qian Mengjia, Zheng Nannan, Liu Yifei, Song Yuanlin
Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University Shanghai Medical College, Shanghai, China.
Cell Biol Toxicol. 2025 Feb 7;41(1):40. doi: 10.1007/s10565-025-09990-w.
Autophagy related genes (ATGs) play essential roles in maintaining cellular functions, although biological and pathological alterations of ATG phenotypes remain poorly understood. To address this knowledge gap, we utilized the single-cell sequencing technology to elucidate the transcriptomic atlas of ATGs in lung diseases, with a focus on lung epithelium and lymphocytes. This study conducted a comprehensive investigation into RNA profiles of ATGs in the lung tissues obtained from healthy subjects and patients with different lung diseases through single-cell RNA sequencing (scRNA-seq), including COVID-19 related acute lung damage, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), systemic sclerosis (SSC), and lung adenocarcinoma (LUAD). Our findings revealed significant variations of ATGs expression across lung epithelial cell subsets, e.g., over-expression of MAPK8 in basal cells, ATG10 in club cells, and BCL2 in a goblet cell subset. The changes of autophagy-related pathways varied between lung epithelial and lymphocyte subsets. We identified the disease-associated changes in ATG expression, including significant alterations in BCL2, BCL2L1, PRKCD, and PRKCQ in inflammatory lung diseases (COPD and IPF), and MAP2K7, MAPK3, and RHEB in lung cancer (LUAD), as compared to normal lung tissues. Key ligand-receptor pairs (e.g., CD6-ALCAM, CD99-CD99) and signaling pathways (e.g., APP, CD74) might serve as biomarkers for lung diseases. To evaluate ATGs responses to external challenges, we examined ATGs expression in different epithelial cell lines exposed to cigarette smoking extract (CSE), lysophosphatidylcholine (lysoPC), lipopolysaccharide (LPS), and cholesterol at various doses and durations. Notable changes were observed in CFLAR, EIF2S1, PPP2CA, and PPP2CB in A549 and H1299 against CSE and LPS. The heterogeneity of ATGs expression was dependent on cell subsets, pathologic conditions, and challenges, as well as varied among cellular phenotypes, functions, and behaviors, and the severity of lung diseases. In conclusion, our data might provide new insights into the roles of ATGs in epithelial biology and pulmonary disease pathogenesis, with implications for disease progression and prognosis.
自噬相关基因（ATGs）在维持细胞功能中起着至关重要的作用，尽管对ATG表型的生物学和病理学改变仍知之甚少。为了填补这一知识空白，我们利用单细胞测序技术来阐明肺部疾病中ATGs的转录组图谱，重点关注肺上皮细胞和淋巴细胞。本研究通过单细胞RNA测序（scRNA-seq）对从健康受试者和患有不同肺部疾病的患者获取的肺组织中ATGs的RNA谱进行了全面调查，这些疾病包括与COVID-19相关的急性肺损伤、特发性肺纤维化（IPF）、慢性阻塞性肺疾病（COPD）、系统性硬化症（SSC）和肺腺癌（LUAD）。我们的研究结果显示，ATGs在肺上皮细胞亚群中的表达存在显著差异，例如，MAPK8在基底细胞中过表达，ATG10在棒状细胞中过表达，BCL2在一个杯状细胞亚群中过表达。自噬相关途径的变化在肺上皮细胞和淋巴细胞亚群之间有所不同。与正常肺组织相比，我们确定了ATG表达中与疾病相关的变化，包括炎症性肺部疾病（COPD和IPF）中BCL2、BCL2L1、PRKCD和PRKCQ的显著改变，以及肺癌（LUAD）中MAP2K7、MAPK3和RHEB的显著改变。关键的配体-受体对（如CD6-ALCAM、CD99-CD99）和信号通路（如APP、CD74）可能作为肺部疾病的生物标志物。为了评估ATGs对外部挑战的反应，我们检测了不同上皮细胞系在不同剂量和持续时间下暴露于香烟烟雾提取物（CSE）、溶血磷脂酰胆碱（lysoPC）、脂多糖（LPS）和胆固醇后ATGs的表达。在A549和H1299细胞中，针对CSE和LPS，观察到CFLAR、EIF2S1、PPP2CA和PPP2CB有显著变化。ATGs表达的异质性取决于细胞亚群、病理状况和挑战，并且在细胞表型、功能和行为以及肺部疾病的严重程度之间也存在差异。总之，我们的数据可能为ATGs在肺上皮生物学和肺部疾病发病机制中的作用提供新的见解，对疾病进展和预后具有重要意义。
