Triglyceride enhancs NSCLC metastasis via lipid β-oxidation by RhoA-driven cytoskeletal remodeling in ECM-constrained microenvironments.

BACKGROUND: Elevated serum triglycerides (TG) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but the mechanisms underlying this association remain unclear. Elucidating the role of TG in NSCLC metastasis may reveal novel therapeutic targets. METHODS: A retrospective analysis was performed in 77 NSCLC patients stratified by serum TG levels. Survival was assessed using Kaplan-Meier analysis, and metastasis rates were compared using chi-square tests. Hypertriglyceridemia was modelled in mice. Extracellular matrix (ECM)-constrained invasion assays were conducted in NSCLC cell lines. Lipid β-oxidation and RhoA signalling were interrogated using pharmacological inhibition and genetic silencing of CPT1A and RhoA. RESULTS: Patients with hypertriglyceridemia (TG > 2.3 mmol/L) had significantly shorter overall survival (log-rank p = 0.009) and higher rates of lymph node metastasis (84.4% vs. 37.9%) and distant metastasis (31.3% vs. 3.4%) than normotriglyceridemic patients (TG < 1.7 mmol/L). Mechanistically, TG enhanced lipid β-oxidation, activating RhoA-driven cytoskeletal remodelling that enabled tumour cells to overcome ECM confinement and acquire metastatic competence. Pharmacological inhibition or genetic silencing of CPT1A or RhoA significantly suppressed TG-induced invasion and metastasis. CONCLUSIONS: Elevated serum TG promotes NSCLC metastasis through a lipid β-oxidation-RhoA-cytoskeletal axis. Targeting lipid catabolism and cytoskeletal dynamics may represent a therapeutic strategy for hypertriglyceridemia-associated NSCLC.