PLA2G4A-driven arachidonic acid metabolic reprogramming promotes NSCLC progression via the HSF1 signaling axis

Aberrant arachidonic acid (AA) metabolism is a hallmark of cancer, and cytosolic phospholipase A2 (PLA2G4A) is the rate-limiting enzyme that initiates this cascade. However, the cell-intrinsic role of PLA2G4A and its downstream signaling mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. Here, we show that PLA2G4A is significantly upregulated in NSCLC patients and cell lines. Gain-of-function experiments in 16HBE normal bronchial epithelial cells demonstrate that ectopic PLA2G4A expression promotes proliferation, induces epithelial-mesenchymal transition, and cooperates with MYC to drive tumor formation in vivo. Conversely, CRISPR-Cas9-mediated knockout of PLA2G4A suppresses cell proliferation, soft agar colony formation, and invasion, while inducing G1 phase arrest and apoptosis. In vivo, PLA2G4A knockout inhibits tumor growth and lung colonization. Mechanistically, transcriptomics and biochemical analysis reveal that PLA2G4A knockout reduces IL-1β expression and suppresses MAPK pathway activity, leading to decreased phosphorylation of heat shock factor 1 (HSF1). Pharmacological inhibition of IL-1β phenocopies these effects, and ectopic HSF1 expression rescues the proliferative defect caused by PLA2G4A ablation. Upstream, we identify SP1 as a candidate transcriptional regulator of PLA2G4A. Collectively, these findings suggest a linear SP1/PLA2G4A/IL-1β/MAPK/HSF1 signaling axis that operates cell-intrinsically to promote NSCLC proliferation, survival, and metastasis. Targeting this pathway may represent a potential therapeutic avenue for NSCLC.