AUTHOR=Yang Kai , Chen MeiFeng , Wu Yao , Duan WenJuan , Huang Na , Zhao Xia , Cheng DeYun 

TITLE=Multi-omics integration identifies ASPH and PTTG1 as potential causal drivers of lung adenocarcinoma progression and immune evasion

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1689275

DOI=10.3389/fimmu.2025.1689275

ISSN=1664-3224

ABSTRACT=BackgroundDespite advances in therapy, lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality. Angiogenesis and immune evasion critically influence LUAD progression and treatment resistance, yet epithelial-derived regulatory mechanisms and causal genes remain unclear.MethodsWe employed single-cell transcriptomics (scRNA-seq) to identify angiogenesis-related epithelial-specific genes in LUAD. Mendelian randomization (MR) analyses utilizing large-scale genomic databases (eQTLGen, FinnGen) established genetic causality. A prognostic risk model was developed and validated using GEO and TCGA cohorts. Western blotting in clinical specimens and functional assays (gene knockdown, proliferation, migration, and invasion) verified core gene functions.ResultsAspartate β-hydroxylase (ASPH) and Pituitary tumor-transforming gene 1 (PTTG1) were identified as causal genes linked to LUAD risk and poor prognosis. Elevated protein expression of ASPH and PTTG1 was confirmed in LUAD tissues. ASPH knockdown significantly inhibited LUAD cell proliferation, migration, and invasion. The ASPH/PTTG1-based risk model robustly predicted prognosis. High-risk patients demonstrated “cold” immune microenvironments characterized by increased stromal infiltration and reduced immune effector cells. These patients also showed heightened sensitivity to several chemotherapeutic and targeted agents, including Cisplatin and Crizotinib.ConclusionIntegrating single-cell sequencing, MR-based causality, clinical validation, and functional experiments, we identified ASPH and PTTG1 as key regulators of LUAD angiogenesis and immune evasion. These findings substantiate ASPH/PTTG1 as promising biomarkers and therapeutic targets, offering new insights into precision therapies integrating anti-angiogenic and immunomodulatory strategies.