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 team, led by Marios G. Krokidis, combined AlphaFold-based structure prediction, the disorder-focused FuzPred algorithm, and HADDOCK molecular docking simulations to compare wild-type FUS with three mutant variants: G156E, R234L, and R521C. Each mutation sits in a different functional region of the 526-residue protein, which is largely built from intrinsically disordered regions — stretches that never settle into one rigid shape but instead constantly sample many conformations. FUS uses this flexibility to bind RNA, regulate transcription, participate in DNA damage repair, and shuttle between the nucleus and cytoplasm.

The structural comparison revealed that none of the mutations causes a dramatic collapse of the protein’s folded domains. Global backbone deviations, measured on high-confidence residues, ranged from about 5.5 angstroms for R234L to roughly 15.4 angstroms for R521C, but these values mostly reflect changes in how the intact folded domains — such as the RNA recognition motif and zinc finger — are oriented relative to one another through flexible linkers, not classical misfolding. The mutations themselves all fall in regions that AlphaFold flags as low-confidence, consistent with their intrinsically disordered character.

More telling were the local measurements. Solvent-accessible surface area calculations showed that all three mutants expose additional surface to the aqueous environment, with G156E and R521C producing the largest increases — 104.24 and 108.44 square angstroms respectively — and strongly negative hydrophobicity-weighted values, indicating that hydrophobic patches are being pushed into contact with water. The authors suggest this creates a thermodynamic drive to bury those patches through aberrant intermolecular aggregation, a route that could push FUS away from its native dynamic state and toward pathological solid-like phase transitions.

The FuzPred analysis sharpened the picture. For each residue, the algorithm estimates the probability of a disorder-to-order transition upon binding (pDO), the probability of remaining disordered (pDD), and the multiplicity of binding modes (MBM), which captures how many different interaction geometries a region can explore. When the researchers subtracted the wild-type profile from each mutant’s, the global differences were tiny — but the local changes within ten residues of each mutation site were clearly visible. All three mutations reduced local pDD and increased local MBM, suggesting a loss of the protein’s healthy, fuzzy binding behavior and a drift toward less coordinated, more promiscuous interaction patterns.

The docking simulations then connected these local disorder changes to concrete functional consequences. For R521C, which sits in the C-terminal proline-tyrosine nuclear localization signal, the team docked the NLS peptide against Transportin-1, the nuclear import receptor that normally carries FUS into the nucleus. The wild-type peptide bound with a HADDOCK score of −87.8 ± 3.4 kcal/mol, while the R521C mutant scored −79.5 ± 3.6 — weaker, despite actually presenting a slightly larger buried surface area. The energy breakdown showed the mutant’s electrostatic contribution dropped sharply, from −382.9 to −264.5 kcal/mol, indicating that replacing a positively charged arginine with cysteine undermines the charge complementarity that drives recognition. This aligns with earlier experimental and computational work showing that R521C reduces Transportin-1 affinity and causes FUS to accumulate in the cytoplasm, a major pathogenic step in ALS.

For G156E, which lies just upstream of the RGG1 RNA-binding domain, the team docked a 60-residue peptide against a 23-nucleotide RNA fragment. The wild-type complex achieved a HADDOCK score of −74.7 ± 1.6 kcal/mol with a buried surface of roughly 1,736 square angstroms, reflecting the multivalent contacts typical of RGG-mediated RNA recognition. The G156E mutant scored −61.6 ± 5.7, with a smaller interface of about 1,401 square angstroms. The authors attribute this to the added glutamate’s negative charge sitting close to the RNA phosphate backbone, increasing electrostatic repulsion and weakening the interaction. Because RGG domains help drive RNA-dependent phase separation and the formation of ribonucleoprotein granules, weakening these contacts could destabilize normal condensates and promote the misregulated RNA metabolism seen in ALS.

R234L, located in the intrinsically disordered RGG2 domain, could not be docked in the conventional sense because no experimentally determined FUS–RNA complex involving that region exists, and standard docking platforms require well-defined structural templates. Instead, the researchers interpreted its effects through the disorder analysis, which showed a local reduction in pDD — a loss of the native, functional flexibility that RGG domains rely on for multivalent RNA recognition. Removing an arginine from this positively charged motif would be expected to diminish both electrostatic attraction and cation–π interactions with RNA, consistent with the mutation’s association with disrupted RNA metabolism.

Taken together, the findings support a view of FUS-related ALS in which pathogenicity arises not from wholesale misfolding but from localized rearrangements in intrinsic disorder, binding versatility, and molecular recognition. Each mutation prunes a different functional modality — R521C compromises nuclear import, G156E weakens RNA binding, R234L erodes RGG2-mediated interactions — yet all three converge on the same cellular outcome: impaired nucleocytoplasmic distribution, altered stress granule behavior, and a tendency toward pathological aggregation. The authors caution that AlphaFold-derived models of intrinsically disordered regions should be treated as plausible conformational hypotheses rather than definitive structures, and they propose extending the approach with molecular dynamics simulations, multiple RNA sequence contexts, and integration with experimental data from NMR, cross-linking, and cellular localization assays. The same computational framework could also be applied to other disordered ALS proteins such as TDP-43 and hnRNPA1, offering a route toward therapies that restore protein localization and RNA homeostasis rather than simply blocking aggregation.

Subject of Research: Computational analysis of how ALS-associated FUS mutations alter conformational dynamics, intrinsic disorder, and molecular interactions

Article Title: ALS-associated FUS mutations induce site-specific alterations in conformational dynamics and molecular interactions

Article References: Amourgianos, C., Exarchos, T. P., Vlamos, P., & Krokidis, M. G. (2026). ALS-associated FUS mutations induce site-specific alterations in conformational dynamics and molecular interactions. Frontiers in Chemical Biology, 5, Article 1851848. https://doi.org/10.3389/fchbi.2026.1851848

Image Credits: AI Generated

DOI: 10.3389/fchbi.2026.1851848

Keywords: ALS, FUS, intrinsically disordered proteins, AlphaFold, FuzPred, HADDOCK, molecular docking, RNA binding, nuclear import, Transportin-1, phase separation, neurodegeneration

The study took advantage of a powerful experimental approach: generating motor neurons from induced pluripotent stem cells (iPSCs) derived from patients with FUS-ALS. These cells carry the same genetic mutation found in patients, allowing researchers to study the disease in a human cellular context rather than relying solely on animal models. Crucially, the team developed methods to separate the cell bodies from the axons of these motor neurons, enabling them to examine gene expression and RNA regulation in each compartment independently. This compartment-specific analysis revealed something unexpected: even in healthy human motor neurons, different regions of the cell use different versions of the 3′ untranslated region (3’UTR)—the portion of messenger RNA that controls protein production and localization. When the researchers compared healthy and FUS-ALS motor neurons, they found that this compartment-specific 3’UTR regulation was disrupted in the disease state, affecting genes such as SNCA, which has previously been implicated in other neurodegenerative conditions including Parkinson’s disease.

Among all the molecular changes the team detected, one stood out for its consistency and magnitude: SLITRK2, a gene encoding a protein normally involved in neuronal development and synapse formation, was strongly and repeatedly upregulated across multiple independent FUS-ALS models. This was not a chance finding in a single cell line or experimental condition; the elevation appeared reliably whenever the researchers examined motor neurons carrying FUS mutations. The consistency of this signal suggested that SLITRK2 might not simply be a bystander in the disease process but could be actively contributing to the axonal and synaptic defects that characterize early FUS-ALS pathology.

To test this hypothesis directly, the researchers used a genetic silencing technique to reduce SLITRK2 expression in the FUS-ALS motor neurons. The results were striking: lowering SLITRK2 levels normalized the axonal defects that had been observed in the diseased neurons. Axons, which in ALS patients begin to degenerate long before muscle weakness becomes apparent, showed measurable improvement when this single gene was suppressed. This finding positions SLITRK2 as a potential therapeutic target—something that could be modulated to slow or prevent the earliest stages of motor neuron decline in this form of ALS.

But axonal health is only part of the story. Motor neurons must ultimately communicate with muscle fibers through specialized connections called neuromuscular junctions, and it is the failure of these junctions that directly produces the muscle weakness and atrophy seen in ALS patients. To investigate whether SLITRK2 reduction could also rescue functional deficits at these connections, the team developed a sophisticated experimental system: a fully iPSC-derived neuromuscular junction model grown in microfluidic chips. These tiny devices compartmentalize motor neurons and muscle cells in separate chambers connected by narrow channels, allowing axons to grow toward the muscle and form functional synapses while keeping the two cell types physically separated. This setup mimics key aspects of the in vivo neuromuscular architecture and enables precise measurement of synaptic transmission.

Using this neuromuscular junction-on-a-chip system, the researchers made a nuanced discovery. When they reduced SLITRK2 in FUS-ALS motor neurons, the signaling between nerve and muscle was significantly rescued—the junctions transmitted electrical and chemical signals more effectively, approaching the levels seen in healthy connections. However, this functional improvement occurred without any change in the physical innervation of the muscle: the number and extent of nerve-muscle contacts remained the same. Additionally, the treatment did not correct the hypo-excitability of the motor neurons themselves—the reduced ability of these cells to fire electrical impulses that is another hallmark of FUS-ALS. This dissociation between functional rescue and structural or excitability correction provides important insight into the disease mechanism: SLITRK2 appears to specifically regulate the synaptic signaling machinery rather than the overall architecture of the neuromuscular junction or the intrinsic electrical properties of the motor neuron.

This selectivity is scientifically significant because it suggests that different aspects of ALS pathology—axonal degeneration, synaptic dysfunction, and altered neuronal excitability—may be driven by partially independent molecular pathways. A therapeutic strategy targeting SLITRK2 could therefore address some symptoms of the disease without necessarily correcting all of them, which has implications for how such treatments might be combined with other approaches in the future. It also underscores the value of the compartment-specific and functional assays the team developed: by measuring axonal morphology, synaptic transmission, and neuronal excitability separately, researchers can begin to disentangle the complex web of cellular defects that contribute to motor neuron loss.

Beyond the SLITRK2 finding itself, the study makes several broader contributions to ALS research. The detailed mapping of compartment-specific 3’UTR expression in human motor neurons provides a reference dataset that other researchers can use to investigate RNA regulation in both healthy and diseased states. The identification of altered 3’UTR isoforms in genes like SNCA across different cellular compartments suggests that RNA processing defects may be a common thread connecting multiple forms of neurodegeneration, not just FUS-ALS. And the fully iPSC-derived neuromuscular junction-on-a-chip model represents a robust new tool for the field—one that can be used to test potential therapeutics in a human-relevant system before moving to animal studies or clinical trials, potentially accelerating the drug development pipeline for this devastating disease.

The work was supported by funding from Stichting ALS Nederland through several collaborative projects, the European research consortia MAXOMOD and INTEGRALS, the ALS CURE project, Alzheimer Nederland, the EU Joint Programme for Neurodegenerative Diseases, Health-Holland, the Netherlands Organization for Scientific Research, the Research Foundation-Flanders, and the Muscular Dystrophy Association. The research team included contributors from the University Medical Center Utrecht Brain Center, the VIB-KU Leuven Center for Neuroscience, Utrecht University, and Erasmus MC University Medical Center in Rotterdam. The corresponding author, R. Jeroen Pasterkamp, led the study from the Department of Translational Neuroscience in Utrecht.

While the findings are promising, they represent an early step in a long translational journey. The experiments were conducted in laboratory-grown human cells, and translating these results into treatments for patients will require extensive further research, including validation in animal models and eventually clinical testing. Nevertheless, the identification of SLITRK2 as a driver of axonal and synaptic deficits in FUS-ALS provides researchers with a concrete molecular target and a clearer picture of how this form of ALS begins its destructive course. As the field continues to unravel the complex biology of motor neuron degeneration, studies like this one—combining human stem cell models, compartment-specific molecular analysis, and functional neuromuscular junction assays—are helping to build the foundation for future therapies that might one day slow, halt, or even reverse the progression of ALS.

Subject of Research: SLITRK2 regulation of axonal and neuromuscular junction deficits in FUS-ALS motor neurons

Article Title: SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons

Article References: de Jongh, R., Wiersema, A. F., van Dijk, C. H., Verdegaal, R. C., Smulders, M. M. J., Basak, O., van Os, J., Peeters, S., Olmedo-Martínez, L., Bloemenkamp, L. M., Garner, K. M., Da Cruz, S., Koppers, M., Iuliano, A., Pijnappel, W. W. M. P., Kenna, K. P., & Pasterkamp, R. J. (2026). SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons. Nature Communications. https://doi.org/10.1038/s41467-026-78419-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78419-7

Keywords: ALS, FUS, SLITRK2, motor neurons, iPSC, neuromuscular junction, axons, 3'UTR, SNCA, neurodegeneration, microfluidics, synaptic signaling

The research, published in Frontiers in Oncology, reviewed twenty consecutive patients treated between August 2013 and May 2024 at the Instituto Português de Oncologia do Porto Francisco Gentil, a comprehensive cancer centre that serves as a national reference centre for soft-tissue sarcomas and a member of the European Reference Network EURACAN. The cohort comprised eleven patients with low-grade fibromyxoid sarcoma, six with sclerosing epithelioid fibrosarcoma, and three with hybrid tumours displaying overlapping histological features of both entities. Every diagnosis was validated by a pathologist with dedicated sarcoma expertise, and the team collected detailed clinical, pathological and molecular data from electronic medical records.

The molecular work relied on two complementary techniques. Fluorescence in situ hybridisation, using break-apart probes, detects rearrangements of the FUS and EWSR1 genes, while a targeted next-generation sequencing panel screens for the specific fusion transcripts that result when these genes splice onto partner genes such as CREB3L1 and CREB3L2. Molecular analysis produced informative results in nineteen of the twenty patients, and FUS or EWSR1 rearrangements were identified in sixteen of them. FUS rearrangements predominated overall, appearing in twelve patients, and were found exclusively in low-grade fibromyxoid sarcomas and hybrid tumours. EWSR1 rearrangements, by contrast, were confined entirely to the sclerosing epithelioid fibrosarcoma group.

That near-complete molecular exclusivity is one of the study’s most striking findings. Among patients tested by sequencing, the FUS::CREB3L2 fusion characterised the FUS-rearranged tumours, while the EWSR1-rearranged sclerosing epithelioid fibrosarcomas harboured either EWSR1::CREB3L1 or EWSR1::CREB3L2 fusions. The authors argue that this pattern argues against a true biological continuum between the two entities, instead supporting relatively distinct molecular profiles within a related tumour spectrum. Hybrid tumours, which share greater molecular overlap with low-grade fibromyxoid sarcoma, nonetheless behaved clinically more like the aggressive end of the spectrum, a discrepancy that carries real implications for how patients are risk-stratified.

MUC4, a protein detected by immunohistochemistry and widely regarded as a highly sensitive and specific diagnostic marker for these tumours, was positive in thirteen of the twenty cases. The lower overall positivity rate of sixty-five percent, driven mainly by the low-grade fibromyxoid sarcoma subgroup, likely reflects methodological factors rather than a true reduction in diagnostic sensitivity, according to the authors. Retrospective binary scoring over a prolonged inclusion period, combined with the focal nature of MUC4 expression in some low-grade tumours, may have understated its presence. The marker remains a cornerstone of diagnosis in a family of cancers so rare that few pathologists encounter more than a handful of cases in a career.

Treatment in the cohort was overwhelmingly surgical. Nineteen of the twenty patients underwent curative-intent resection, with complete excision and negative margins achieved in fifteen cases. Radiotherapy was used selectively: one patient received radical-intent treatment and three received adjuvant radiotherapy, delivered with modern techniques such as volumetric modulated arc therapy or three-dimensional conformal radiotherapy to total doses of 66 to 70 Gy. Only one patient, a case of sclerosing epithelioid fibrosarcoma that had already spread to bone at diagnosis, received systemic therapy, progressing through doxorubicin, an etoposide and ifosfamide combination, and finally the kinase inhibitor pazopanib, each discontinued for progressive disease. The limited role of chemotherapy mirrors the modest benefit conventional sarcoma regimens have shown against these tumours.

After a median follow-up of sixty-five months, the outcomes split cleanly along histological lines. Local recurrence occurred in only two patients, one with sclerosing epithelioid fibrosarcoma and one with a hybrid tumour, at a median of thirty-two months after initial treatment. Distant metastases developed in three patients, all with sclerosing epithelioid fibrosarcoma or hybrid histology, and the median time to metastatic spread was a startlingly short six months. Every one of these events was associated with adverse pathological features, including high cellularity, nuclear atypia and elevated mitotic counts, and the two metastasising sclerosing epithelioid fibrosarcomas also carried EWSR1 rearrangements. Not a single patient with pure low-grade fibromyxoid sarcoma relapsed during the study period.

Survival figures underscore the same divide. At last follow-up, all eleven patients with low-grade fibromyxoid sarcoma and all three with hybrid tumours were alive, the hybrid patient who developed lung metastases having been rendered disease-free by complete metastasectomy. One patient with sclerosing epithelioid fibrosarcoma died of disease progression, making it the sole disease-related death in the cohort and leaving overall survival at ninety-five percent. Median overall survival was not reached during the study window, which extended to January 2026. The authors caution, however, that the small number of events limits statistical power and that these observations should be treated as hypothesis-generating rather than definitive prognostic evidence.

The findings align closely with larger international datasets. A French nationwide registry study of 330 patients published in the European Journal of Cancer found metastases present at diagnosis in thirty percent of sclerosing epithelioid fibrosarcomas versus four percent of low-grade fibromyxoid sarcomas, while a twenty-seven-institution international study reported in the American Journal of Surgical Pathology confirmed the more indolent behaviour of the low-grade entity. The Portuguese series, though small, contributes something the larger studies often lack: systematic and concordant testing by both fluorescence in situ hybridisation and next-generation sequencing, a median follow-up exceeding five years, and multidisciplinary diagnostic validation at a European reference centre, a setting under-represented in the existing literature.

The practical message for clinicians is one of vigilance calibrated to risk. The authors suggest that hybrid tumours be managed clinically as high-risk, in line with sclerosing epithelioid fibrosarcoma, irrespective of their predominant molecular profile, and that sclerosing epithelioid fibrosarcomas showing adverse features, such as more than four mitoses per ten high-power fields, hypercellularity, nuclear atypia, necrosis or dedifferentiation, warrant close and sustained surveillance. Long-term follow-up remains essential, as documented recurrences and metastases in these tumours can emerge years or even decades after the initial diagnosis, meaning the sixty-five-month median follow-up of this study may not capture the full natural history. Because no single centre can accumulate meaningful numbers of such rare cancers, the researchers emphasise that collaborative multicentre efforts with consistent molecular assessment will be vital to refine prognostic stratification and, ultimately, to guide the development of targeted therapies for a group of tumours whose genetics are now far better mapped than their treatment options.

Subject of Research: Clinical and molecular behaviour of low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma across a spectrum of ultra-rare soft-tissue sarcomas

Article Title: Low-grade fibromyxoid and sclerosing epithelioid fibrosarcoma: distinct behaviour in the same spectrum of ultra-rare sarcomas

Article References: Castanheira, B., Soldin, I., Vieira, J., Afonso, M., Conde, S., Moreira, A., & Abreu, M. H. (2026). Low-grade fibromyxoid and sclerosing epithelioid fibrosarcoma: distinct behaviour in the same spectrum of ultra-rare sarcomas. Frontiers in Oncology, 16, Article 1943496. https://doi.org/10.3389/fonc.2026.1943496

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1943496

Keywords: low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma, sarcoma, FUS, EWSR1, MUC4, gene fusions, hybrid tumours, ultra-rare cancer, metastasis, EURACAN, next-generation sequencing

Recent experiments have established that condensate interfaces are not passive bystanders in amyloid formation. In condensates formed by the low-complexity domain of the RNA-binding protein hnRNPA1, and in droplets of the ALS-linked protein FUS, fibril formation is strongly enhanced at the droplet surface rather than in the interior. Other condensate systems suppress aggregation by sequestering proteins inside, or redirect it by altering the structural polymorphism of amyloid-forming proteins like Tau and Aβ. What has remained unclear is which molecular and physical variables select among these outcomes. The new work tackles this question with a purpose-built simulation framework called flux-driven molecular dynamics, or FD-MD, which allows the researchers to independently tune chain architecture, chain rigidity, and the transport of molecules toward a condensate interface.

The model is deliberately minimal. Each protein is represented as a 25-bead coarse-grained polymer with two bead types arranged in a repeating block pattern, analogous to a simple block copolymer. Like beads attract one another through Lennard-Jones potentials, while unlike beads repel. Crucially, the two internal blocks of cohesive beads are stiffened by harmonic angular potentials, making them behave like rigid rods that stand in for β-prone, aggregation-prone motifs, while the intervening linkers remain floppy. This design separates cohesion from stiffness: a chain can be made more rigid without increasing its attraction strength, and the placement of its sticky motifs can be rearranged without changing the total amount of cohesive material. The simulations do not resolve residue-level chemistry, strand registry, or hydrogen-bond directionality, so the filaments they produce are coarse-grained analogs of amyloid rather than atomically resolved structures.

The simulation geometry mimics a driven cellular environment. Two semi-arrested condensate surfaces, built from 8,000 chains of the same molecular species, face each other across a dilute region. Up to 20,000 additional chains are then introduced at a prescribed deposition rate, each given an initial velocity directed toward the nearest interface—an initial kick that mimics the chemical-potential gradient dragging molecules toward the droplet surface in a living cell. Without this bias, inserted molecules would simply diffuse and aggregate in the dilute phase. Together, the deposition rate and the initial drift velocity define a minimal flux protocol for probing how non-equilibrium delivery shapes interfacial assembly.

The first major finding concerns rigidity. When chains with stiff β-prone segments were deposited onto the condensate interface, they formed anisotropic protrusions that extended away from the surface, elongated over time, bundled together, and eventually formed mesh-like structures capable of bridging the two opposing interfaces. Chains with the identical bead pattern but floppy backbones accumulated at the interface just as readily, yet relaxed into laterally spreading, disordered surface aggregates with no fibrillar character. Because the two simulations differed only in angular stiffness, the comparison identifies backbone rigidity as the variable that converts ordinary interfacial adsorption into directional fibrillar growth. When the researchers scrambled the placement of cohesive beads at fixed composition, the chains failed to form filaments altogether and instead promoted the growth of extended planar surfaces, underscoring that motif patterning matters as much as motif count.

Why does stiffness matter so much? The answer lies in the orientational field imposed by the interface itself. By measuring a nematic order parameter as a function of distance from the surface, the researchers found that condensate interfaces organize arriving chains into a layered structure before any large-scale assembly begins. Segments that directly contact the surface lie flat in the interfacial plane, approaching the theoretical planar limit of the order parameter within the first few bead diameters. Beyond this contact layer, the order parameter does not decay monotonically; instead, it alternates with a characteristic spacing of roughly eight bead diameters, with positive maxima indicating segments preferentially aligned along the interface normal. This spacing matches the separation between successive rod-like units along an extended chain, meaning that outer segments of surface-anchored chains project into the dilute region while their leading segments remain adsorbed. The result is a layered architecture—a planar contact layer followed by segments oriented outward—that is precisely the local arrangement a protruding fibril needs in order to elongate.

The second major axis of control is molecular flux. Material arriving at a condensate interface can be incorporated in two geometrically distinct ways: it can spread laterally, increasing surface coverage, or it can extend outward, increasing the height and volume of the growing assembly. Tracking the exposed area and convex-hull volume of the largest adsorbed cluster, the researchers showed that increasing the initial drift velocity dramatically accelerates surface coverage—reducing the time to reach a coverage shoulder from roughly 1,000 chain insertions at the slowest drift to about 300 at the fastest. But faster arrival came with a cost. When the researchers measured the elongation rate of individual filaments along their principal axis, they found that the longitudinal growth rate decreased systematically as the initial drift velocity increased, while the transverse thickening of the filaments depended only weakly on it. Faster molecules, in other words, cover the surface quickly but are less efficiently incorporated into the growing fibril tip.

The likely explanation is a competition between two fates for incoming chains. Chains that attach along the lateral surface of an existing protrusion mainly increase its radial extent, whereas chains captured near the filament tip contribute directly to axial elongation. A large initial drift velocity promotes rapid interfacial capture and surface coverage, starving the protrusion tip of material that could otherwise drive extension. The deposition rate and drift velocity act together to select the growth trajectory: frequent deposition favors protrusive growth when the initial drift is weak, whereas large drift velocities bias the system toward lateral spreading and suppress out-of-plane extension. Aging in this model, the authors conclude, is not a single pathway but a family of non-equilibrium trajectories selected by how material is delivered to, and captured by, the condensate interface.

The broader implications are considerable. Because sequence-encoded rigidity and molecular delivery are, in principle, independently tunable—through protein engineering on one hand and through expression level, exchange kinetics, transport, or chemical remodeling on the other—the framework suggests that aging trajectories of condensates could be redirected by modulating molecular delivery alone, without altering the protein sequence itself. The authors also propose mesoscale observables that bridge their simulations to experiments: convex-hull geometry to separate lateral coverage from anisotropic extension, a molecular loading ratio that reports how accumulated material distributes over the exposed aggregate area, and the gyration-tensor spectrum that identifies persistent symmetry breaking along the filament axis. These quantities do not require residue-level resolution and can be compared directly with microscopy-based morphology measurements.

The researchers are careful to note the limits of their abstraction. The model does not define a critical nucleus or measure nucleation rates and barriers, so they use the term interfacial fibril initiation rather than claiming to resolve a specific nucleation pathway. Each point in their morphology map corresponds to a single trajectory, making the map descriptive rather than a thermodynamic phase diagram, and the fibrils themselves are coarse-grained assemblies stabilized by cohesion and rigidity rather than residue-resolved amyloid. Still, the core message is clear and testable: the same protein can age along entirely different morphological routes simply because the rate and manner of molecular delivery change. If this separation between structural competence and transport control holds in cellular condensates, it opens a practical route to intervening in the earliest stages of amyloid disease—not by redesigning the proteins involved, but by changing how fast they arrive at the droplet surface where fibrils are born.

Subject of Research: Simulation study of how chain rigidity, motif patterning, and molecular flux control fibril growth at biomolecular condensate interfaces

Article Title: β motifs and molecular flux promote fibril growth at condensate interfaces

Article References: Biswas, S., & Potoyan, D. A. (2026). β motifs and molecular flux promote fibril growth at condensate interfaces. iScience, 29(11), Article 117855. https://doi.org/10.1016/j.isci.2026.117855

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117855

Keywords: biomolecular condensates, amyloid fibrils, phase separation, molecular dynamics, protein aggregation, condensate aging, β-sheet motifs, molecular flux, hnRNPA1, FUS, neurodegenerative disease, coarse-grained simulation

Phase separation is the physical phenomenon by which a well-mixed solution splits into distinct phases, the way oil separates from vinegar in a shaken bottle of salad dressing. In cells, proteins containing intrinsically disordered, low-complexity domains can drive the formation of membraneless compartments called condensates, which concentrate specific molecules without any enclosing lipid membrane. Nucleoli, stress granules and nuclear speckles all form this way. The key property of healthy condensates is dynamism: molecules diffuse in and out, and the entire assembly can dissolve within seconds or minutes once conditions change. This liquid-like behavior depends on weak, multivalent interactions among the low-complexity domains, which constantly break and reform.

The trouble begins when those weak interactions stop being weak and transient. The review describes how, in ALS, condensates formed by RNA-binding proteins such as FUS and TDP-43 progressively lose their reversibility, maturing from liquid droplets into gel-like states and eventually into solid fibrillar aggregates that are hallmarks of the diseased motor neuron. This liquid-to-solid transition, sometimes called pathological hardening, is driven by the same low-complexity domains that make condensates form in the first place. Given time, the transient beta-sheet-like contacts within these domains can lock into stable structures, converting a dynamic organelle into an irreversible inclusion that the cell cannot dismantle.

What makes the new review distinctive is its emphasis on the layers of cellular regulation that normally prevent this maturation. The authors assemble evidence that molecular chaperones, best known for helping newly made proteins fold, also patrol condensates. Heat shock protein 70 family members, for example, can bind exposed hydrophobic stretches within condensates, remodel their internal organization and keep the assemblies fluid. Chaperone activity thereby extends the window in which a condensate remains reversible, buying the cell time to dissolve it before aggregation becomes permanent. When chaperone capacity is overwhelmed or declines, as it does with age and stress, that window narrows.

Nuclear import receptors form a second, perhaps more surprising, line of defense. Karyopherin-beta2, the receptor that ferries FUS into the nucleus, does more than transport. It binds directly to the proline-tyrosine nuclear localization signal within FUS and, in doing so, physically shields the low-complexity domain from engaging in the multivalent contacts that drive phase separation and fibrillization. In effect, the import receptor acts as a portable anti-aggregation chaperone, keeping FUS soluble during its journeys through the cytoplasm. The review highlights how this mechanism illustrates a broader principle: compact folded domains can modulate the behavior of disordered regions they are physically linked to or bound against.

The proteostasis network supplies a third layer of regulation. Enzymatic components such as protein disulfide isomerase and peptidyl-prolyl cis-trans isomerase A can alter the conformational state of proteins inside or near condensates, while ubiquilin-like protein 2, an ALS-linked protein, helps shuttle ubiquitinated cargo between condensates and the protein degradation machinery. Optineurin, another ALS-associated factor, participates in autophagic clearance of aggregates. Together these systems form a quality-control pipeline that continuously remodels and removes material from condensates, limiting the residence time of any given molecule and thereby reducing the probability that transient contacts will ripen into stable aggregates.

The review then turns to one of the most devastating genetic insults in ALS: the hexanucleotide repeat expansion in the C9ORF72 gene, the most common known cause of familial disease. This expansion produces arginine-rich dipeptide repeat proteins, and these short, highly basic peptides are potent modifiers of phase behavior. They can seed the condensation of RNA-binding proteins and, critically, impair nuclear import pathways, including the transport receptors that keep FUS in check. The result is a double hit: more condensation is promoted at the same time as the systems that would normally reverse it are disabled. The authors present this as a mechanistic explanation for why C9ORF72 pathology so closely resembles the FUS and TDP-43 proteinopathies seen across the ALS spectrum.

Perhaps the most forward-looking section of the review concerns zinc finger domains. Recent structural and biophysical studies suggest that these small, compact, folded modules can recognize specific polymer states of low-complexity domains and constrain their growth. Rather than dissolving condensates outright, zinc finger domains appear to cap or crosslink the polymers in ways that limit further elongation and material transition. This supports what the authors describe as a model in which structured domains act as modulators of higher-order assemblies, reading the physical state of a condensate and restraining its maturation. If confirmed across multiple ALS-associated proteins, this recognition mechanism could represent an entirely new regulatory vocabulary that cells use to manage their liquid organelles.

The therapeutic implications are considerable. Most ALS drug development has targeted downstream events, such as oxidative stress, excitotoxicity or the aggregates themselves. The framework laid out by the Nara Medical University team suggests an upstream strategy: preserve or restore condensate homeostasis. Enhancing chaperone activity, boosting nuclear import, supporting proteostasis components or mimicking the polymer-capping behavior of zinc finger domains could all, in principle, keep pathological proteins in their reversible, harmless state before fibrils ever form. Because the same regulatory principles appear to govern TDP-43, FUS and C9ORF72-related pathology, a therapy aimed at condensate homeostasis might cut across the genetic subtypes of the disease rather than addressing them one by one.

Cautious optimism is warranted. The review is a synthesis of mechanistic studies rather than a demonstration of efficacy in patients, and the authors themselves frame their conclusions as a model to be tested: clarifying how chaperones, import receptors, proteostasis enzymes and structured domains operate across ALS-associated proteins remains the task ahead. Yet the conceptual shift is hard to overstate. ALS, on this view, is not merely a disease of misfolded proteins but a disease of lost reversibility, in which the cell’s capacity to keep its own internal liquids liquid has been eroded. Understanding and reinforcing that capacity may prove to be one of the most promising directions in the search for effective treatments.

Subject of Research: Regulation of biological phase separation by molecular chaperones and related factors in amyotrophic lateral sclerosis

Article Title: Regulation of biological phase separation by molecular chaperones and related factors in amyotrophic lateral sclerosis

Article References: Iguchi, N., Isozumi, N., Sugie, K., & Mori, E. (2026). Regulation of biological phase separation by molecular chaperones and related factors in amyotrophic lateral sclerosis. BMC Medicine. https://doi.org/10.1186/s12916-026-05261-5

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05261-5

Keywords: amyotrophic lateral sclerosis, phase separation, molecular chaperones, TDP-43, FUS, C9ORF72, nuclear import, proteostasis, protein aggregation, RNA-binding proteins, zinc finger domains, condensates