Abstract
Lung adenocarcinoma (LUAD) with epidermal growth factor receptor (EGFR) mutations is prevalent in East Asian NSCLC patients and responds initially to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but resistance inevitably develops. This study identifies ATP-binding cassette subfamily A member 3 (ABCA3) as a key protein involved in tumor progression and TKI resistance in EGFR-mutant cancers. ABCA3 was significantly upregulated in EGFR-mutant LUAD cells compared to WT, promoting cell viability, proliferation, migration, and clonogenicity, while suppressing apoptosis. Mechanistic analyses revealed that ABCA3 enhanced cholesterol uptake and activated the PI3K/AKT/mTOR pathway, contributing to tumor growth. Moreover, the transcription factor SP1 was found to induce ABCA3 expression, especially following EGFR-TKI treatment. ABCA3 was markedly elevated in EGFR-TKI-resistant cell line, and its inhibition restored drug sensitivity. These findings suggest that ABCA3 plays a central role in mediating both tumor progression and resistance in EGFR-mutant LUAD. Targeting ABCA3 may represent a promising strategy to suppress tumor growth and overcome EGFR-TKI resistance, providing a novel therapeutic avenue for patients with EGFR-mutated non-small cell lung cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-026-04221-6.