Li Yue, Ma Keru, Wang Hao, Liu Zongying, Li Zhuying
Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 26 of Heping Road, Xiangfang District, Harbin, 150040, China.
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
Discov Oncol. 2025 Jun 7;16(1):1028. doi: 10.1007/s12672-025-02835-2.
Lung adenocarcinoma (LUAD) remains associated with limited effective pharmacological treatment options. This study aimed to identify potential therapeutic targets for LUAD through the integration and analysis of multi-omics datasets.
A meta-analysis was conducted using two extensive proteomics datasets, the UK Biobank Proteomics Project (UKB-PPP) and the Fenland study, to identify disease-associated targets for LUAD through the Summary-Data-Based Mendelian Randomization method. Sensitivity analysis, including heterogeneity tests for dependent instruments, were conducted to validate the findings. The prognostic relevance of the identified candidate targets was assessed using transcriptomic data. Functional interactions were explored via protein-protein interaction network analysis, while single-cell analyses were employed to determine cell-specific expression patterns and differentiation trajectories. Potential side effects and therapeutic indications of these targets were evaluated using phenome-wide association studies and pharmacological data mining.
Following meta-analysis, a primary significant target, intercellular adhesion molecule 5 (ICAM5), along with potential targets FUT8 and KLK13, were identified as therapeutic candidates for LUAD. FUT8 demonstrated a positive association with LUAD risk (OR = 1.02, p = 0.049), while ICAM5 (OR = 0.88, p = 0.002) and KLK13 (OR = 0.85, p = 0.021) exhibited negative associations. ICAM5 was further identified as an independent prognostic factor for patient survival (HR: 0.788, 95% CI: 0.663-0.936, p = 0.007) and revealed significant diagnostic and prognostic utility in LUAD. ICAM5 expression correlated with various immune infiltration patterns, suggesting potential modulation of the tumor immune microenvironment. Single-cell analysis revealed that ICAM5 did not directly impact LUAD cell differentiation, though its downstream target, MUC1, may contribute to differentiation processes, particularly in KRAS-mutated LUAD. Furthermore, phenome-wide association studies did not reveal substantial evidence of adverse phenotypes linked to ICAM5, supporting its safety profile for drug development.
ICAM5 emerges as a promising biological marker with significant prognostic and therapeutic potential in LUAD.
肺腺癌（LUAD）的有效药物治疗选择仍然有限。本研究旨在通过整合和分析多组学数据集来确定LUAD的潜在治疗靶点。
使用两个广泛的蛋白质组学数据集，即英国生物银行蛋白质组学项目（UKB-PPP）和芬兰特研究，进行荟萃分析，通过基于汇总数据的孟德尔随机化方法确定LUAD的疾病相关靶点。进行了敏感性分析，包括对相关工具的异质性检验，以验证研究结果。使用转录组数据评估所确定的候选靶点的预后相关性。通过蛋白质-蛋白质相互作用网络分析探索功能相互作用，同时采用单细胞分析来确定细胞特异性表达模式和分化轨迹。使用全表型关联研究和药理数据挖掘评估这些靶点的潜在副作用和治疗适应症。
荟萃分析后，主要显著靶点细胞间粘附分子5（ICAM5）以及潜在靶点FUT8和KLK13被确定为LUAD的治疗候选靶点。FUT8与LUAD风险呈正相关（OR = 1.02，p = 0.049），而ICAM5（OR = 0.88，p = 0.002）和KLK13（OR = 0.85，p = 0.021）呈负相关。ICAM5被进一步确定为患者生存的独立预后因素（HR：0.788，95%CI：0.663 - 0.936，p = 0.007），并在LUAD中显示出显著的诊断和预后效用。ICAM5表达与多种免疫浸润模式相关，提示对肿瘤免疫微环境的潜在调节作用。单细胞分析显示，ICAM5并不直接影响LUAD细胞分化，但其下游靶点MUC1可能有助于分化过程，特别是在KRAS突变的LUAD中。此外，全表型关联研究未发现与ICAM5相关的不良表型的实质性证据，支持其在药物开发中的安全性。
ICAM5是一种有前景的生物标志物，在LUAD中具有显著的预后和治疗潜力。
