Molecular biology reports · 2026
lncRNA HOTAIR promotes airway remodeling by regulating metabolic reprogramming through the FUS/HK2 axis in airway smooth muscle cells.
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Xu Qianqian, Liu Yang, Huang Yongjian, Han Fei
Аннотация
BACKGROUND: Airway remodeling is a critical pathological feature of chronic airway diseases and is closely associated with irreversible airflow limitation. Increasing evidence indicates that metabolic reprogramming contributes to airway smooth muscle cell (ASMC) remodeling; however, the underlying regulatory mechanisms remain incompletely understood.
METHODS: Human ASMCs were stimulated with platelet-derived growth factor-BB (PDGF-BB) to establish an in vitro remodeling model. HOTAIR expression was manipulated using siRNA-mediated knockdown, while FUS and HK2 were restored by plasmid overexpression. Cell viability, proliferation, migration, glycolytic metabolism, and remodeling-associated protein expression were assessed using CCK-8, EdU staining, Transwell assays, Seahorse extracellular flux analysis, qRT-PCR, and western blotting. RNA immunoprecipitation (RIP) and mRNA stability assays were performed to investigate the interaction among HOTAIR, FUS, and HK2.
RESULTS: HOTAIR expression was significantly upregulated in PDGF-BB-stimulated ASMCs. HOTAIR knockdown markedly inhibited ASMC proliferation, migration, and ECM remodeling, with reduced expression of Collagen I, Fibronectin, MMP9, and α-SMA. HOTAIR silencing suppressed glucose uptake, lactate production, ATP generation, and ECAR while partially restoring mitochondrial oxidative phosphorylation. FUS directly bound both HOTAIR and HK2 mRNA; HOTAIR depletion accelerated HK2 mRNA degradation, whereas FUS restoration rescued HK2 mRNA stability. Re-expression of either FUS or HK2 reversed the inhibitory effects of HOTAIR silencing on glycolytic metabolism and ASMC remodeling phenotypes.
CONCLUSION: HOTAIR promotes PDGF-BB-induced glycolytic reprogramming and airway smooth muscle remodeling by stabilizing HK2 mRNA through the RNA-binding protein FUS. T These findings suggest that the HOTAIR/FUS/HK2 axis contributes to PDGF-BB-induced ASMC remodeling and may represent a potential therapeutic target.
METHODS: Human ASMCs were stimulated with platelet-derived growth factor-BB (PDGF-BB) to establish an in vitro remodeling model. HOTAIR expression was manipulated using siRNA-mediated knockdown, while FUS and HK2 were restored by plasmid overexpression. Cell viability, proliferation, migration, glycolytic metabolism, and remodeling-associated protein expression were assessed using CCK-8, EdU staining, Transwell assays, Seahorse extracellular flux analysis, qRT-PCR, and western blotting. RNA immunoprecipitation (RIP) and mRNA stability assays were performed to investigate the interaction among HOTAIR, FUS, and HK2.
RESULTS: HOTAIR expression was significantly upregulated in PDGF-BB-stimulated ASMCs. HOTAIR knockdown markedly inhibited ASMC proliferation, migration, and ECM remodeling, with reduced expression of Collagen I, Fibronectin, MMP9, and α-SMA. HOTAIR silencing suppressed glucose uptake, lactate production, ATP generation, and ECAR while partially restoring mitochondrial oxidative phosphorylation. FUS directly bound both HOTAIR and HK2 mRNA; HOTAIR depletion accelerated HK2 mRNA degradation, whereas FUS restoration rescued HK2 mRNA stability. Re-expression of either FUS or HK2 reversed the inhibitory effects of HOTAIR silencing on glycolytic metabolism and ASMC remodeling phenotypes.
CONCLUSION: HOTAIR promotes PDGF-BB-induced glycolytic reprogramming and airway smooth muscle remodeling by stabilizing HK2 mRNA through the RNA-binding protein FUS. T These findings suggest that the HOTAIR/FUS/HK2 axis contributes to PDGF-BB-induced ASMC remodeling and may represent a potential therapeutic target.