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

The research, led by Audra R. Barnes-Lanier and John C. Chappell at Virginia Tech’s Fralin Biomedical Research Institute, provides the first detailed look at how these soluble receptor variants behave in the developing placenta of both mice and humans. The team documented progressively increasing pericyte coverage of fetoplacental capillaries across gestation, confirmed that placental pericytes display the same phenotypic diversity seen in the brain, heart, and lungs, and then demonstrated that soluble PDGFRβ isoforms are produced at both the RNA and protein levels throughout pregnancy. Most intriguingly, their functional experiments suggest these soluble fragments can modulate the very signaling pathway that recruits pericytes to nascent blood vessels in the first place.

Pericytes are specialized mural cells that wrap around capillaries, reinforcing vessel integrity and coordinating vascular maturation through intimate communication with endothelial cells. The primary chemical conversation between these two cell types runs through platelet-derived growth factor-BB, or PDGF-BB, which endothelial cells display on their surfaces to attract PDGFRβ-bearing pericytes. Decades of genetic work have shown that this pathway must be calibrated with extraordinary precision. Too little PDGF-BB signaling and pericytes abandon the vessel wall, leaving fragile, leaky, hemorrhage-prone capillaries; in mice, loss of PDGF-B or PDGFRβ produces placental abnormalities among a constellation of developmental defects. Too much signaling, on the other hand, drives pericyte hyperproliferation, vascular malformations, and fibrosis, as seen in patients carrying activating PDGFRB mutations.

Soluble receptor isoforms have emerged as one way biology walks this tightrope. Across the receptor tyrosine kinase family, truncated receptor variants generated by alternative mRNA splicing or proteolytic cleavage can act as decoys, sponging up ligand or interfering with full-length receptor activity. The most celebrated example is soluble Flt-1, or sFlt-1, which restrains VEGF-A signaling during vascular sprouting and, when misregulated in the placenta, becomes a central driver of preeclampsia. Until recently, however, soluble PDGFRβ was largely viewed as a degradation product, a biomarker of pericyte damage detected in the aging and diseased brain rather than a molecule with a job of its own. That view began to shift when the Chappell laboratory and collaborators showed that alternatively spliced sPDGFRβ transcripts and proteins are produced under entirely normal developmental conditions.

In the new work, the team turned to the placenta to ask whether these variants might matter during pregnancy. Examining mouse placentas at embryonic days 9.5, 14.5, and 18.5, they found that NG2-positive pericytes appear alongside the earliest vasculogenic structures and progressively invest the expanding capillary network, matching the pace of endothelial growth. Transcriptional analysis confirmed rising expression of pericyte genes including Cspg4, Acta2, and full-length Pdgfrβ across gestation, alongside coordinated changes in the Vegfa, Flt-1, and Pdgfb pathways. Western blotting revealed parallel increases in both the full-length receptor, at roughly 160 kilodaltons, and truncated soluble isoforms. Human placenta samples from uncomplicated full-term pregnancies told the same story, with full-length PDGFRβ and a shorter, soluble variant present in every quadrant examined, though with notable regional heterogeneity across the organ.

To dissect how sPDGFRβ is regulated and what it does, the researchers exploited a murine trophoblast and embryonic stem cell differentiation model, or TESC model, that recapitulates key features of early placental vascular development. As these stem cells differentiated, they formed primitive vascular networks containing fluorescently labeled endothelial cells and pericyte progenitors, while also generating trophoblast lineage cells marked by cytokeratins and the tight junction protein ZO-1, mirroring the cellular constituents of the developing placenta. Within this system, soluble PDGFRβ proteins appeared and accumulated alongside full-length receptor during vessel formation, accompanied by transcripts encoding intron-4 and intron-10 truncation variants previously characterized in the healthy brain.

The regulation experiments yielded two unexpected findings. First, blocking the metalloprotease ADAM10, long implicated in shedding soluble PDGFRβ from damaged pericytes, had no effect on soluble receptor levels during early vessel formation, and instead increased full-length receptor abundance, suggesting that in the developmental context, alternative mRNA splicing rather than proteolytic cleavage is the dominant source. Second, exogenous growth factors failed to boost sPDGFRβ production; adding VEGF-A or PDGF-BB to the cultures actually lowered soluble isoform levels slightly, while PDGF-BB significantly reduced full-length receptor, consistent with ligand-induced receptor internalization and degradation. Hypoxia, however, proved to be a powerful stimulus, driving a robust and sustained increase in soluble PDGFRβ protein after just 12 hours at 3 percent oxygen, and again at 48 hours, while full-length receptor remained unchanged.

That hypoxic sensitivity may be the key to the whole story, because low oxygen tension is a defining feature of early placentation and a hallmark of placental insufficiency. To test whether elevated sPDGFRβ could actually influence PDGF-BB signaling, the team added a soluble receptor mimetic, a peptide spanning the PDGF-BB ligand-binding domain, to their developing vascular networks. As expected, excess PDGF-BB alone reduced full-length PDGFRβ levels while increasing phosphorylation of the receptor at a key regulatory tyrosine residue. But when the mimetic was co-administered, both effects were attenuated, pulling receptor abundance and phosphorylation back toward baseline. The result supports a model in which soluble PDGFRβ acts as a negative feedback modulator, buffering PDGF-BB signaling against overshoot, particularly when hypoxia threatens to destabilize the system.

The implications reach well beyond basic vascular biology. Pericyte dysfunction at the maternal-fetal interface is increasingly implicated in preeclampsia, fetal growth restriction, and the abnormal, poorly perfused vessels that characterize placental insufficiency, conditions that also elevate sFlt-1 and disrupt maternal cardiovascular health. If sPDGFRβ proves to be similarly misregulated in pathological pregnancies, it could serve as both a biomarker for stratifying at-risk patients and a therapeutic target for stabilizing fetoplacental vascular maturation. The authors also point to broader questions about why pericytes diversify into contractile and non-contractile subtypes across organs, and how RNA-binding proteins and splicing factors orchestrate soluble receptor production. Follow-on studies are already planned to validate sPDGFRβ transcript and protein structures, screen disease databases for associations with placental dysfunction, and determine whether the same oxygen-sensitive feedback loop protects, or fails to protect, the fragile vasculature of pregnancies under stress.

The placenta offers an unusually instructive setting in which to study soluble receptor biology because its oxygen environment changes dramatically over the course of gestation. Early placentation occurs under relatively low oxygen tension, a physiological state that protects the developing embryo from oxidative damage while the fetoplacental circulation is still being assembled. The observation that hypoxia robustly increased soluble PDGFRβ production in the TESC model, without altering full-length receptor abundance, suggests that the placenta may naturally encounter conditions that favor soluble isoform generation precisely when vascular remodeling is most active. This oxygen-sensitive behavior distinguishes sPDGFRβ from many other signaling modulators whose expression is driven primarily by ligand availability.

The distinction between alternatively spliced and proteolytically shed soluble receptor variants carries practical consequences for future research. Shed receptor fragments released from damaged pericytes have historically been interpreted as passive markers of injury, whereas splice-derived isoforms represent deliberate gene products that can be regulated independently of cell death or membrane cleavage. The finding that ADAM10 inhibition did not reduce soluble receptor levels during early vessel formation, and instead raised full-length receptor abundance, implies that the developmental placenta relies on transcriptional mechanisms rather than ectodomain shedding. This matters therapeutically, because strategies targeting metalloprotease activity would be unlikely to influence a splicing-derived soluble pool, while interventions aimed at splicing factors or RNA-binding proteins might.

The TESC differentiation model itself deserves attention as a methodological advance. Placental tissue is difficult to obtain and study experimentally, particularly at early developmental stages, and animal models do not fully capture human trophoblast biology. A system in which trophoblast lineage cells, endothelial cells, and pericyte progenitors arise together and assemble vascular-like networks provides a tractable platform for testing how individual signaling components behave in a placental context. The demonstration that soluble PDGFRβ isoforms appear in this model at both transcript and protein levels, matching what is seen in native mouse and human tissue, strengthens confidence that the model reflects genuine developmental regulation rather than an artifact of cell culture.

Several questions remain open before these findings can be translated. The functional experiments relied on a mimetic peptide spanning the ligand-binding domain, so it is not yet certain that endogenously produced soluble isoforms exert identical effects in vivo. The precise stoichiometry between soluble receptor, PDGF-BB ligand, and membrane-bound PDGFRβ that produces meaningful modulation of signaling has not been defined. Whether soluble PDGFRβ sequesters ligand directly, competes for receptor binding, or acts through some other mechanism also remains to be resolved. Answering these questions will require genetic models in which soluble isoform production can be selectively manipulated, allowing investigators to separate the contributions of splicing-derived variants from the full-length receptor they appear to regulate.

Subject of Research: Regulation of PDGF-BB signaling in placental pericytes by soluble PDGFRβ isoforms during fetoplacental vascular development

Article Title: Regulation of PDGF-BB signaling in placental pericytes by soluble PDGFRβ isoforms: implications for fetoplacental vascular development

Article References: Barnes-Lanier, A. R., Duggan, E. C., Dunkenberger, R. A., Lessard, C. V., Cosma, C. C., Steele, C. R., Taylor, S. V., Darden, J. A., Whitham, M. D., Durica, A. R., & Chappell, J. C. (2026). Regulation of PDGF-BB signaling in placental pericytes by soluble PDGFRβ isoforms: implications for fetoplacental vascular development. Angiogenesis, 29(4), Article 67. https://doi.org/10.1007/s10456-026-10091-3

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10091-3

Keywords: placenta, pericytes, PDGF-BB, PDGFRβ, soluble receptor, angiogenesis, fetal development, hypoxia, endothelial cells, preeclampsia, vascular development, alternative splicing