The IGF2BP3-FASN axis drives lipid metabolic reprogramming to promote brain colonization in non-small cell lung cancer.

Abstract

Brain metastases represent a significant cause of morbidity and mortality in non-small cell lung cancer (NSCLC), with limited therapeutic options. The unique brain microenvironment, characterized by low lipid availability, may drive NSCLC cells to adapt through lipid metabolic reprogramming. In this study, we identify a novel mechanism by which IGF2BP3-driven lipid metabolism promotes the brain colonization of NSCLC cells through the IGF2BP3-FASN axis. Elevated IGF2BP3 expression in NSCLC brain metastases correlates with poor prognosis and promotes cancer cell migration, invasion, and brain colonization by activating the lipogenesis pathway. We further identified that FASN was a downstream target of IGF2BP3 in NSCLC cells. Mechanistically, IGF2BP3 binds to FASN mRNA, enhancing its stability through RNA-binding activity. FASN is essential for neutral lipid accumulation and brain colonization, as demonstrated in vitro and in vivo. Our findings highlight the critical role of IGF2BP3 in lipid metabolism and propose that targeting IGF2BP3 may provide a promising therapeutic strategy for NSCLC brain colonization.