FOXA1 Upregulates HILPDA to Enhance Lipid Droplet Accumulation and Anoikis Resistance in Lung Adenocarcinoma

ABSTRACT Lung adenocarcinoma (LUAD) metastasis is a major cause of patient mortality, with the key mechanism being the resistance of tumor cells to anoikis. HILPDA is associated with tumor progression, but its role and mechanism in anoikis in LUAD remain unclear. Bioinformatics analysis and single‐cell sequencing dataset analysis were performed to investigate HILPDA expression in LUAD and its prognostic value, with its expression in cells validated. An anoikis‐resistant A549 cell line variant (A549‐AR) was established, and the effects of HILPDA on its resistance, migration, and invasion were assessed using CCK‐8, trypan blue staining, flow cytometry, wound healing assay, and transwell. Western blot (WB) confirmed protein expression changes. Immunofluorescence microscopy revealed HILPDA's colocalization with lipid droplets, and Oil Red O staining and biochemical assays quantified lipid accumulation. Bioinformatics screening identified FOXA1 as a potential upstream regulator of HILPDA. ChIP‐qPCR and dual‐luciferase reporter assays validated the regulatory role of FOXA1 over HILPDA. A xenograft mouse model was used to evaluate tumor size and lipid accumulation. In LUAD, HILPDA expression was distinctly elevated, correlating with a worse prognosis. Silencing HILPDA markedly curtailed the viability, proliferation, migration, and invasion of A549‐AR cells, and weakened their anti‐apoptotic capacity. HILPDA overexpression bolstered malignancy by augmenting lipid droplet accumulation. FOXA1 transcriptionally activated HILPDA, which increased lipid droplet accumulation and promoted anoikis resistance and metastatic potential in A549‐AR cells. FOXA1 promotes lipid droplet accumulation by transcriptionally activating HILPDA, leading to LUAD anoikis resistance and metastasis. HILPDA may serve as a potential therapeutic target for LUAD metastasis.