Unveiling plumbagin as a novel metabolic modulator to suppress ACC1-mediated de novo lipogenesis in non-small cell lung cancer

Background Targeting tumor metabolic reprogramming, particularly de novo lipogenesis (DNL) regulated by acetyl-CoA carboxylase 1 (ACC1), constitutes a promising therapeutic strategy. Non-small cell lung cancer (NSCLC) is a predominant subtype of lung cancer, characterized by limited treatment options and poor prognosis. Plumbagin (PLB), a natural naphthoquinone, exhibits broad antitumor activity. However, its direct targets and mechanisms in NSCLC remain unclear. Purpose This study aims to identify the molecular targets of PLB and elucidate its antitumor mechanism in NSCLC. Methods High-resolution mass spectrometry, in conjunction with a biotin-labeled PLB probe, was utilized to identify the direct targets of PLB. Surface plasmon resonance (SPR), streptavidin-based immunoprecipitation, and molecular dynamics simulation were employed to confirm the direct interaction between PLB and ACC1. ACC1 knockdown NSCLC cells were generated using siRNAs, followed by colony formation, wound-healing, and transwell assays. Tissue microarray analysis of clinical NSCLC samples was conducted to assess ACC1 expression and its clinical relevance. Lipid metabolites in NSCLC cells and tissues were quantified using an ELISA, and lipid droplet formation was observed via BODIPY staining. The in vivo therapeutic efficacy of PLB was evaluated using NSCLC xenograft models. Results Proteomic analysis identified ACC1 as a direct PLB target. Binding assays and SPR analyses confirmed the specific interaction between PLB and ACC1, and structural simulations revealed that PLB binds to the carboxyltransferase domain of ACC1 with high affinity. Importantly, tissue microarray analysis revealed that ACC1 was significantly overexpressed in tumor tissues of patients with NSCLC, and high expression of ACC1 was positively correlated with poor prognosis. Mechanistically, PLB inhibited the ACC1/FASN/SCD1 lipogenic axis, resulting in a substantial reduction in lipid metabolites and lipid droplet accumulation. Furthermore, exogenous palmitic acid supplementation partially reversed the antitumor effects of PLB, whereas ACC1 knockdown synergistically enhanced PLB’s antitumor efficacy. In NSCLC xenograft models, PLB significantly inhibited tumor growth by targeting the ACC1/FASN/SCD1 pathway and reducing key lipid metabolites. Conclusion Our findings identify PLB as a novel ACC1 inhibitor that suppresses NSCLC by targeting the ACC1/FASN/SCD1 axis-mediated DNL pathway, highlighting its potential as a metabolic modulator for NSCLC therapy.