Hidden RNA Switch Drives Airway Remodeling Through a Metabolic FUS/HK2 Axis

Deep inside the walls of chronically diseased airways, a quiet molecular coup is underway. Airway smooth muscle cells, the muscular scaffolding that constricts and relaxes bronchial tubes, abandon their normal contractile identity and morph into proliferative, migratory, matrix-secreting engines. This transformation, known as airway remodeling, is the pathological bedrock of chronic airway diseases such as asthma, and it is closely tied to the irreversible airflow limitation that no inhaler can undo. Now, a team of researchers in Wuhan, China, has traced a specific chain of command that orchestrates this process, and their findings point to an unexpected alliance between a long non-coding RNA, an RNA-binding protein, and a glycolytic enzyme. The study, published in Molecular Biology Reports, reveals that the lncRNA HOTAIR promotes airway smooth muscle remodeling by stabilizing the mRNA of hexokinase 2 through the RNA-binding protein FUS, thereby rewiring cellular metabolism toward glycolysis.

The research, led by Qianqian Xu, Yang Liu, Yongjian Huang, and Fei Han from Tongji Hospital and Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, focused on a phenomenon that has captivated cell biologists for decades: metabolic reprogramming. Healthy, quiescent airway smooth muscle cells rely predominantly on mitochondrial oxidative phosphorylation to meet their energy demands. But when these cells are stimulated by platelet-derived growth factor-BB, or PDGF-BB, a potent growth factor implicated in airway remodeling, they undergo a dramatic metabolic shift. They ramp up glucose uptake, accelerate lactate production, and generate ATP through glycolysis even in the presence of oxygen, a hallmark of the Warburg-like phenotype more commonly associated with cancer cells. This glycolytic switch is not merely a byproduct of the remodeling process; it is a driver of it, fueling the proliferation, migration, and extracellular matrix deposition that thicken airway walls and narrow bronchial lumens.

What makes the new study particularly compelling is the identity of the master regulator behind this metabolic coup. HOTAIR, short for HOX transcript antisense RNA, is a long non-coding RNA that does not encode a protein but instead functions as a regulatory molecule. It first rose to prominence in cancer biology, where it was shown to promote metastasis and drug resistance in breast cancer and to drive carcinogenesis across multiple tumor types. More recently, HOTAIR has been implicated in vascular smooth muscle cell proliferation in carotid artery stenosis, and in promoting glycolysis through GLUT1 upregulation via mTOR signaling in cancer cells. But its role in airway smooth muscle cells had remained largely unexplored until now. The Wuhan team found that HOTAIR expression was significantly upregulated in human airway smooth muscle cells stimulated with PDGF-BB, suggesting that this lncRNA is a key player in the remodeling response.

To dissect the mechanism, the researchers established an in vitro remodeling model by stimulating human airway smooth muscle cells with PDGF-BB. They then silenced HOTAIR using siRNA-mediated knockdown and observed the consequences. The results were striking. HOTAIR depletion markedly inhibited cell proliferation, as measured by CCK-8 and EdU staining, and suppressed cell migration in Transwell assays. It also reduced the expression of remodeling-associated proteins, including Collagen I, Fibronectin, MMP9, and α-SMA, the molecular signatures of extracellular matrix deposition and smooth muscle phenotypic switching. In other words, removing HOTAIR pulled the cells back from their remodeling identity and restored a more quiescent state.

But the most revealing part of the story came when the researchers examined cellular metabolism. Using Seahorse extracellular flux analysis, they found that HOTAIR silencing suppressed glucose uptake, lactate production, ATP generation, and the extracellular acidification rate, or ECAR, the key readout of glycolytic flux. At the same time, it partially restored mitochondrial oxidative phosphorylation, the energy pathway that quiescent airway smooth muscle cells normally favor. This metabolic reversal was not a side effect of reduced proliferation; it was a direct consequence of HOTAIR’s role in maintaining the glycolytic program. The findings suggest that HOTAIR is not merely a passenger in the remodeling process but a metabolic conductor, actively reprogramming airway smooth muscle cells toward the Warburg-like phenotype that fuels airway wall thickening.

The next question was how HOTAIR achieves this metabolic reprogramming at the molecular level. The answer lies in a tripartite interaction involving the RNA-binding protein FUS and the glycolytic enzyme hexokinase 2, or HK2. FUS, a member of the FET family of RNA-binding proteins, is known for its roles in DNA repair, stress granule formation, and the regulation of mRNA stability. It has also been implicated in pulmonary artery smooth muscle cell proliferation through the suppression of GRM1 expression. Using RNA immunoprecipitation, the researchers demonstrated that FUS directly binds both HOTAIR and HK2 mRNA. This dual binding is the crux of the mechanism: HOTAIR acts as a scaffold that recruits FUS to HK2 mRNA, thereby protecting it from degradation.

The evidence for this model is elegant. When the researchers depleted HOTAIR, HK2 mRNA was rapidly degraded, leading to reduced HK2 protein expression and diminished glycolytic flux. But when they restored FUS by plasmid overexpression, HK2 mRNA stability was rescued, and the glycolytic program was re-established. Re-expression of either FUS or HK2 reversed the inhibitory effects of HOTAIR silencing on glycolytic metabolism and airway smooth muscle remodeling phenotypes. This rescue experiment is the smoking gun that confirms the HOTAIR/FUS/HK2 axis as a functional pathway. It also explains why HK2, the rate-limiting enzyme of glycolysis, is so critical to the remodeling process. HK2 has been shown to couple glycolysis to the profibrotic actions of TGF-beta in other cell types, and to drive airway inflammation in experimental asthma through the regulation of airway epithelial cell apoptosis. Its role in airway smooth muscle cells now appears to be equally pivotal.

The implications of this work extend beyond basic cell biology. Airway remodeling is the critical pathological feature that separates reversible airflow limitation from the irreversible kind, and it is the reason why some patients with chronic airway disease never fully recover lung function despite aggressive anti-inflammatory therapy. Current treatments target inflammation and bronchoconstriction but do little to halt the structural changes in the airway wall. If the HOTAIR/FUS/HK2 axis can be pharmacologically modulated, it could represent a new therapeutic frontier. The researchers suggest that this pathway may represent a potential therapeutic target, and their findings open the door to strategies that either silence HOTAIR, disrupt its interaction with FUS, or inhibit HK2 activity in airway smooth muscle cells. Such approaches would attack the remodeling process at its metabolic root, rather than merely managing its downstream consequences.

It is worth noting that the study was performed entirely in vitro, using established cell lines and a PDGF-BB stimulation model. The researchers themselves acknowledge that the findings suggest, rather than prove, the relevance of this axis in human disease. Translating these results into clinical practice will require validation in primary airway smooth muscle cells from patients with asthma and other chronic airway diseases, as well as in animal models of airway remodeling. The researchers also note that the datasets used and analyzed during the study are available from the corresponding author on reasonable request, and that the research received no external funding. The authors declare no competing interests, and the study did not involve any human participants or animals, so no ethical approval was required.

Nevertheless, the study adds a crucial piece to the emerging picture of airway remodeling as a metabolically driven process. It joins a growing body of evidence that metabolic reprogramming is not a bystander but a central regulator of airway smooth muscle cell behavior. Previous work has shown that p62-dependent autophagy in airway smooth muscle cells regulates metabolic reprogramming and promotes airway remodeling, and that midkine promotes PDGF-BB-induced proliferation, migration, and glycolysis of airway smooth muscle cells via the PI3K/Akt pathway. The new study now reveals that a long non-coding RNA can orchestrate this metabolic switch by stabilizing the mRNA of a key glycolytic enzyme through an RNA-binding protein. This adds a new layer of post-transcriptional regulation to the remodeling process and suggests that the non-coding transcriptome, long dismissed as biological dark matter, may hold the keys to understanding and ultimately treating the structural changes that make chronic airway disease so stubbornly irreversible. The HOTAIR/FUS/HK2 axis, in short, is a molecular chain of command that transforms airway smooth muscle cells from metabolic bystanders into glycolytic engines of remodeling, and it may well be the target that the field has been searching for.

Subject of Research: Molecular Biology

Article Title: lncRNA HOTAIR promotes airway remodeling by regulating metabolic reprogramming through the FUS/HK2 axis in airway smooth muscle cells

Article References: Xu, Q., Liu, Y., Huang, Y., & Han, F. (2026). lncRNA HOTAIR promotes airway remodeling by regulating metabolic reprogramming through the FUS/HK2 axis in airway smooth muscle cells. Molecular Biology Reports, 53(1), Article 1723. https://doi.org/10.1007/s11033-026-12879-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12879-4

Keywords: HOTAIR, airway remodeling, airway smooth muscle cells, metabolic reprogramming, glycolysis, FUS, HK2, asthma, lncRNA, PDGF-BB, promotes, airway