On the interface of fatty acid metabolism: A crosstalk between fatty acid ω-hydroxylase CYP4F11 and fatty acid desaturase 2 in non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths worldwide with non-small cell lung cancer (NSCLC) as the predominant subtype. Drug resistance in patients with NSCLC often limits treatment effectiveness, underscoring the need for novel therapeutic targets. We have previously demonstrated that a knockdown of CYP4F11 attenuates the proliferation and migration of NCI-H460 cells. CYP4F11 is a fatty acid ω-hydroxylase and metabolizes arachidonic acid to the important lipid mediator 20-hydroxyeicosatetraenoic acid. However, the underlying mechanism of how CYP4F11 promotes cancer progression is unknown. Here, we first confirmed that a genetic ablation of CYP4F11 reduces cell proliferation and migration in an additional NSCLC cell line. Conversely, CYP4F11 overexpression markedly enhanced proliferation and migration in both cell models, underlining the relevance of CYP4F11 as a putative drug target. To further examine the impact of CYP4F11, transcriptomic profiling was conducted comparing CYP4F11 knockdown and control cells. Most intriguingly, fatty acid desaturase 2 (FADS2), a key enzyme in arachidonic acid biosynthesis, was one of the most significantly downregulated genes. Further validation confirmed a significant downregulation of FADS2 at both mRNA and protein levels in CYP4F11 knockdown cells, while a CYP4F11 overexpression triggered its expression. This suggests a regulatory mechanism between CYP4F11 and FADS2 through the joint metabolite arachidonic acid. Collectively, our studies identify CYP4F11 as a promoter of NSCLC cell proliferation and migration and establish a crosstalk between CYP4F11 and FADS2. This work provides new mechanistic insights into lipid metabolism-driven oncogenesis and highlights CYP4F11 as a promising therapeutic target for NSCLC. SIGNIFICANCE STATEMENT: CYP4F11 promotes non-small cell lung cancer progression by driving cell proliferation and migration, as evidenced by both loss-of-function and gain-of-function assays. Importantly, we for the first time identified a positive association between CYP4F11 and fatty acid desaturase 2, uncovering a previously unrecognized tumorigenic mechanism at the cancer-lipid metabolism interface that provides new opportunities for targeted intervention.