Li Hong-Xia, Fei Jing, Xu Wei, Peng Yi, Yan Pi-Jun, Xu Yong, Qin Gang, Teng Fang-Yuan
Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, and Metabolic Vascular Diseases Key Laboratory of Sichuan-Chongqing Cooperation, Luzhou, Sichuan 646000, China.
Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
Int Immunopharmacol. 2025 May 8;154:114509. doi: 10.1016/j.intimp.2025.114509. Epub 2025 Mar 29.
Regulated cell death (RCD), a genetically controlled process mediated by specialized molecular pathways (commonly termed programmed cell death), plays pivotal roles in diverse pathophysiological processes. However, the landscape and functional implications of RCD subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly characterized. This study aimed to systematically investigate the involvement of RCD mechanisms in the pathogenesis and progression of CRSwNP.
Transcriptomic datasets (GSE136825, GSE23552, GSE198950, GSE196169, GSE156285) related to CRSwNP were retrieved from the Gene Expression Omnibus (GEO) database. A comprehensive panel of 18 RCD-associated gene sets was compiled through a systematic literature review. Gene set variation analysis (GSVA) was employed to profile RCD activation patterns in CRSwNP. Integrative bioinformatics approaches including weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression were implemented to identify hub RCD-related genes and construct a cell death index (CDI). Single-cell RNA sequencing (scRNA-seq) data were analyzed to map RCD dynamics across cellular subpopulations. Clinical validation was performed using qRT-PCR quantification of key genes in nasal polyp/inferior turbinate tissues, with the concurrent assessment of symptom severity via visual analogue scale (VAS) scores.
GSVA revealed significant upregulation of 8 RCD subtypes in CRSwNP: apoptosis, ferroptosis, necroptosis, entotic cell death, lysosome-dependent cell death, NETosis, immunogenic cell death, and anoikis. Pathway enrichment analysis demonstrated that RCD-related differentially expressed genes were predominantly involved in epithelial-mesenchymal transition (EMT) and immune-inflammatory regulation. Furthermore, the WGCNA algorithm and LASSO analysis identified 8 key cell death genes (PTHLH, GRINA, S100A9, SCG2, HMOX1, RNF183, TYROBP, SEMA7A), which were utilized to construct the cell death-related index (CDI). In training and validation cohorts, the CDI was significantly elevated in CRSwNP compared to control and exhibited high diagnostic performance, with elevated scores correlating with enhanced immune cell infiltration. Single-cell resolution analysis uncovered cell type-specific RCD activation patterns. Clinical validation confirmed significantly higher expression of S100A9, PTHLH, and HMOX1 in eosinophilic versus non-eosinophilic polyps. Notably, expression levels of PTHLH, S100A9, HMOX1, GRINA, and TYROBP showed strong positive correlations with VAS scores.
Our investigation delineates an RCD activation signature in CRSwNP pathogenesis, characterized by 8 key cell death modalities and their regulatory genes. The novel CDI exhibits promising diagnostic potential, while mechanistic insights suggest RCD pathways may drive disease progression through EMT potentiation and inflammatory cascade amplification. These findings provide a framework for developing RCD-targeted therapeutic strategies in CRSwNP.
调节性细胞死亡（RCD）是一种由特定分子途径介导的基因控制过程（通常称为程序性细胞死亡），在多种病理生理过程中起关键作用。然而，RCD亚型在伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP）中的情况及其功能意义仍未得到充分表征。本研究旨在系统地研究RCD机制在CRSwNP发病机制和进展中的作用。
从基因表达综合数据库（GEO）中检索与CRSwNP相关的转录组数据集（GSE136825、GSE23552、GSE198950、GSE196169、GSE156285）。通过系统的文献综述，编制了一组包含18个与RCD相关的基因集。采用基因集变异分析（GSVA）来描绘CRSwNP中RCD的激活模式。实施了包括加权基因共表达网络分析（WGCNA）和最小绝对收缩和选择算子（LASSO）回归在内的综合生物信息学方法，以识别关键的RCD相关基因并构建细胞死亡指数（CDI）。分析单细胞RNA测序（scRNA-seq）数据，以描绘不同细胞亚群中的RCD动态。使用qRT-PCR对鼻息肉/下鼻甲组织中的关键基因进行定量，并通过视觉模拟量表（VAS）评分同时评估症状严重程度，进行临床验证。
GSVA显示CRSwNP中有8种RCD亚型显著上调：凋亡、铁死亡、坏死性凋亡、内吞性细胞死亡、溶酶体依赖性细胞死亡、中性粒细胞胞外陷阱形成、免疫原性细胞死亡和失巢凋亡。通路富集分析表明，与RCD相关的差异表达基因主要参与上皮-间质转化（EMT）和免疫炎症调节。此外，WGCNA算法和LASSO分析确定了8个关键的细胞死亡基因（PTHLH、GRINA、S100A9、SCG2、HMOX1、RNF183、TYROBP、SEMA7A），这些基因被用于构建细胞死亡相关指数（CDI）。在训练和验证队列中，与对照组相比，CRSwNP中的CDI显著升高，并且具有较高的诊断性能，分数升高与免疫细胞浸润增加相关。单细胞分辨率分析揭示了细胞类型特异性的RCD激活模式。临床验证证实，嗜酸性息肉与非嗜酸性息肉相比，S100A9、PTHLH和HMOX1的表达显著更高。值得注意的是，PTHLH、S100A9、HMOX1、GRINA和TYROBP的表达水平与VAS评分呈强正相关。
我们的研究描绘了CRSwNP发病机制中的RCD激活特征，其特征为8种关键的细胞死亡方式及其调控基因。新型CDI具有良好的诊断潜力，而机制研究表明，RCD途径可能通过增强EMT和放大炎症级联反应来驱动疾病进展。这些发现为开发针对CRSwNP的RCD靶向治疗策略提供了框架。
