FAAH initiates a positive feedback loop to promote lung adenocarcinoma progression through inhibition of ferroptosis.

Ferroptosis represents an iron-dependent form of cell death characterized by accumulation of lipid peroxides. However, it is largely elusive how authentic lipid metabolites contribute to ferroptosis, and whether this is dysregulated in malignant cells due to metabolic rewiring. Here, we identify fatty acid amide hydrolase (FAAH) as a crucial ferroptosis regulator in lung adenocarcinoma (LUAD). FAAH is upregulated and correlated with poor prognosis of LUAD patients. FAAH overexpression inhibits ferroptosis, whereas FAAH knockdown robustly enhances ferroptosis of LUAD cells. Mechanistically, FAAH promotes the palmitoylation of STAT3 through converting N-palmitoylethanolamine to palmitic acid. Palmitoylated STAT3 undergoes cytomembrane translocation and phosphorylation by JAK2, and transcriptionally activates GPX4 to suppress ferroptosis. Concomitantly, activated STAT3 licenses FAAH transcription, thus forming a positive feedback loop in LUAD cells. FAAH targeting represses tumor growth and boosts the anti-tumor efficacy of cisplatin in vivo. These findings uncover a novel regulatory circuit of ferroptosis driven by a saturated fatty acid, and demonstrate the applicability of targeting FAAH to overcome ferroptosis resistance in LUAD therapy.