Respiratory research · 2026
Mechanism study of RUNX1/NSUN2 upregulating fatty acid-binding protein 5 through 5-methylcytosine methylation to mediate lipid metabolic reprogramming to promote immunotherapy resistance in non-small cell lung cancer.
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He Changjun, Li Yingbin, He Haowen, Zhou Fucheng, Fu Bicheng, Bu Jianlong, Wang Mingyu, Kong Xianglong, Li Pengju, Ni Boxiong, Xu Shidong
Аннотация
OBJECTIVE: This study explored the mechanism of RUNX1/NSUN2/FABP5 promoting immunotherapy resistance in non-small cell lung cancer (NSCLC).
METHODS: NSCLC patients received anti-programmed cell death protein 1 (PD-1) therapy. In vitro A549 and NCI-H520 cells and in vivo xenograft mouse models were established. RUNX1, NSUN2, FABP5, PD-L1, and lipid metabolic profiles were analyzed using RT-qPCR, Western blot, and biochemical assays. Gain- and loss-of-function experiments were performed to assess the roles of RUNX1, FABP5, and NSUN2 in NSCLC. CD8+ T cells in tumor tissues were assessed through flow cytometry. A NSCLC cell-CD8⁺ T cell co-culture system was established, with T cell activation and effector cytokine secretion determined. The mechanism of the RUNX1/NSUN2/FABP5 axis in NSCLC was elucidated by dual-luciferase, ChIP, MeRIP, RIP, and Actinomycin D assays.
RESULTS: RUNX1 was highly expressed in immunotherapy-resistant NSCLC. RUNX1 was positively correlated with elevated serum lipids and negatively associated with CD8⁺ T cell activation in tumor tissues. RUNX1 promoted PD-L1 expression and resistance to anti-PD-1 therapy in vivo via FABP5-mediated lipid metabolic reprogramming. RUNX1 regulated FABP5-mediated lipid metabolic reprogramming, enhanced PD-L1 expression, and induced CD8⁺ T cell dysfunction. FABP5 knockdown inhibited lipid metabolism and partially reversed the effects of RUNX1 in NSCLC. RUNX1 promoted NSUN2 transcription, which in turn increased m⁵C methylation of FABP5 and enhanced FABP5 mRNA stability. NSUN2 knockdown partially averted RUNX1's effect in NSCLC.
CONCLUSION: RUNX1 alters m⁵C methylation levels by regulating NSUN2 transcription to promote FABP5-mediated lipid metabolic reprogramming, which in turn enhances PD-L1 expression and consequently induces immune resistance in NSCLC.
METHODS: NSCLC patients received anti-programmed cell death protein 1 (PD-1) therapy. In vitro A549 and NCI-H520 cells and in vivo xenograft mouse models were established. RUNX1, NSUN2, FABP5, PD-L1, and lipid metabolic profiles were analyzed using RT-qPCR, Western blot, and biochemical assays. Gain- and loss-of-function experiments were performed to assess the roles of RUNX1, FABP5, and NSUN2 in NSCLC. CD8+ T cells in tumor tissues were assessed through flow cytometry. A NSCLC cell-CD8⁺ T cell co-culture system was established, with T cell activation and effector cytokine secretion determined. The mechanism of the RUNX1/NSUN2/FABP5 axis in NSCLC was elucidated by dual-luciferase, ChIP, MeRIP, RIP, and Actinomycin D assays.
RESULTS: RUNX1 was highly expressed in immunotherapy-resistant NSCLC. RUNX1 was positively correlated with elevated serum lipids and negatively associated with CD8⁺ T cell activation in tumor tissues. RUNX1 promoted PD-L1 expression and resistance to anti-PD-1 therapy in vivo via FABP5-mediated lipid metabolic reprogramming. RUNX1 regulated FABP5-mediated lipid metabolic reprogramming, enhanced PD-L1 expression, and induced CD8⁺ T cell dysfunction. FABP5 knockdown inhibited lipid metabolism and partially reversed the effects of RUNX1 in NSCLC. RUNX1 promoted NSUN2 transcription, which in turn increased m⁵C methylation of FABP5 and enhanced FABP5 mRNA stability. NSUN2 knockdown partially averted RUNX1's effect in NSCLC.
CONCLUSION: RUNX1 alters m⁵C methylation levels by regulating NSUN2 transcription to promote FABP5-mediated lipid metabolic reprogramming, which in turn enhances PD-L1 expression and consequently induces immune resistance in NSCLC.
Предметные рубрики MeSH
Carcinoma, Non-Small-Cell LungHumansLung NeoplasmsAnimalsMiceFatty Acid-Binding ProteinsMetabolic ReprogrammingUp-RegulationCore Binding Factor Alpha 2 Subunit5-MethylcytosineLipid MetabolismA549 CellsDrug Resistance, NeoplasmMaleMethyltransferasesImmunotherapyMice, NudeXenograft Model Antitumor AssaysFemaleMice, Inbred BALB CRepressor ProteinsCell Line, Tumor