Luo_2026_J.Cancer_17_99

Metabolic reprogramming is an important feature in non-small cell lung cancer (NSCLC) that can result in therapeutic resistance. Exploring dysregulated lipid metabolism in NSCLC will accelerate the development of potential lipid biomarkers to target and control the malignant progression of NSCLC. In this study, RNA next-generation sequencing of 25 paired NSCLC specimens and adjacent normal tissues was used to find that carboxylesterase 3 (CES3) was upregulated in NSCLC. Knockdown of CES3 significantly inhibited NSCLC cell proliferation and invasion. Additionally, CES3 inhibition promoted lipid accumulation in NSCLC cells. Furthermore, we found transcription factor AP-2alpha (TFAP2A) could regulate CES3 levels in NSCLC. TFAP2A was found upregulated in NSCLC and correlated with poorer outcome. Inhibiting TFAP2A resulted in suppressed cell proliferation as well as invasion while increasing the lipid accumulation in NSCLC. CES3 overexpression could reverse the impact of TFAP2A inhibition on NSCLC progression. In summary, TFAP2A dysregulation resulted in CES3 overexpression and the following NSCLC tumorigenesis. Targeting the TFAP2A/CES3 axis may represent a promising therapeutic strategy for NSCLC in the future.