APOA1 as a Potential Therapeutic Target and Novel Biomarker in Lung Adenocarcinoma

ABSTRACT Apolipoprotein A1 (APOA1), the main structural protein of high‐density lipoprotein, has been implicated in cancer, but its role in lung adenocarcinoma (LUAD) remains unclear. Here, we integrate pan‐cancer and LUAD‐focused multi‐omics with patient‐serum validation, in‐vitro and in‐vivo functional assays, and drug‐response/immune‐infiltration analyses to define the role of APOA1. Public datasets (TCGA, HPA, UALCAN, cBioPortal) were used to profile expression, alterations, epigenetics, immune infiltration (CIBERSORT), and pathways (GO/KEGG/GSEA). Serum APOA1 was quantified in 60 LUAD and 30 healthy subjects. APOA1 was overexpressed in A549 and SPCA1 cells to assess proliferation, migration, and invasion; xenografts evaluated in‐vivo growth. Drug‐sensitivity correlations were analyzed. APOA1 is downregulated in LUAD and associates with worse survival; serum levels are reduced. Diagnostic performance was high (AUC = 0.942). APOA1 overexpression suppressed proliferation, migration, and invasion in vitro and reduced tumor volume in vivo. High APOA1 linked to complement/coagulation cascades and distinct immune infiltration. Drug sensitivity analysis revealed enhanced efficacy of agents like selumetinib in high‐APOA1 tumors. This integrated, cross‐layer evidence positions APOA1 as a tumor suppressor and actionable biomarker in LUAD, with implications for early detection, therapeutic stratification, and immunomodulatory strategies.