Perfluorononanoic acid enhances non-small cell lung cancer progression through CD36-driven fatty acid metabolic reprogramming.

Lung cancer ranks among the most prevalent and deadly malignant tumors globally, posing a significant threat to human health. Perfluorononanoic acid (PFNA), as an emerging persistent organic pollutant, has attracted widespread attention due to its extensive presence in the environment. However, the effect of PFNA on lung cancer development and its molecular mechanism have not been reported. This study utilized A549 and H1299 non-small cell lung cancer cell lines to examine the toxicological impact of environmentally relevant PFNA concentrations. The results showed that PFNA exposure significantly enhanced the proliferative capacity of A549 and H1299 cells. Further studies revealed that PFNA promoted fatty acid uptake in lung cancer cells, and detection of fatty acid transporter expression showed that CD36 expression was significantly upregulated. PFNA facilitated the epithelial-mesenchymal transition (EMT) in lung cancer cells. Mechanistic studies revealed that PFNA promotes fatty acid uptake by upregulating CD36 expression, thereby activating the mTOR signaling pathway. PFNA notably enhanced lung cancer cells' resistance to cisplatin-induced ferroptosis. In-depth mechanistic studies found that PFNA inhibits cisplatin-induced ferroptosis by promoting GPX4 expression. In vivo animal models confirmed that PFNA exposure promotes lung cancer progression. This study identifies a novel mechanism where environmentally relevant PFNA concentrations affect lung cancer cell proliferation by modulating fatty acid metabolism, offering insights for assessing PFNA-related lung cancer risk and potential targets for prevention and treatment. This study investigates the role of PFNA in lung cancer, focusing on its interaction with CD36 and the mTOR signaling pathway.