The study centers on a long-standing puzzle in regenerative medicine. Decellularized adipose matrix, a scaffold material stripped of cells from donor fat tissue, has shown a remarkable ability to spur new fat formation at transplantation sites while provoking little immune rejection. Yet its performance has been inconsistent, with new fat cells appearing only near blood vessels at the edges of grafts. The researchers hypothesized that the true active ingredients were not the scaffold’s structural fibers themselves but nanoscale vesicles embedded within the extracellular matrix, known as matrix-bound nanovesicles, or MBVs. These vesicles, first identified in various tissue scaffolds, carry protective cargoes of microRNAs, proteins, and lipids that allow the matrix to communicate with surrounding cells.

To test this idea, the team isolated adipose-derived MBVs using two fundamentally different processing routes. One batch came from chemically decellularized fat tissue, treated with detergents and oxidizing agents; the other came from mechanically concentrated fat extracellular matrix, produced by homogenization and fine filtration. Under the transmission electron microscope, both types displayed the characteristic cup-shaped, bilayer-membrane morphology of extracellular vesicles, with most particles measuring under 200 nanometers in diameter. But the similarities ended there. The mechanically derived vesicles, dubbed M-AT-MBVs, were recovered at roughly 7.1 times the yield of their chemically prepared counterparts from the same amount of starting tissue, suggesting that harsh chemical processing destroys a substantial fraction of these nanoscale messengers.

Functional testing in the laboratory revealed even starker differences. When human adipose-derived stem cells were cultured with the vesicles, both types pushed the cells toward fat formation, but the mechanically derived vesicles produced significantly stronger upregulation of PPAR-gamma, a master regulator of adipogenesis, approaching the levels seen with a commercial differentiation cocktail. The mechanically derived vesicles also outperformed in migration assays, speeding wound closure in stem cell monolayers. In parallel experiments with human umbilical vein endothelial cells, the same vesicles stimulated the formation of tubular networks on Matrigel, a standard proxy for new blood vessel growth, again with the mechanically prepared particles showing clear superiority.

Identifying the active ingredient was only half the battle. Free vesicles injected into the body would diffuse away and degrade before they could orchestrate meaningful tissue formation, so the researchers engineered a delivery vehicle. Using a capillary microfluidic platform, they fabricated uniform hydrogel microspheres from methacrylated hyaluronic acid, a photo-crosslinkable derivative of a natural matrix component. Because the bare microsphere surface offered few binding sites for vesicles, the team coated the spheres with polydopamine, an adhesive polymer inspired by mussel proteins. The coating transformed the carriers: vesicle loading more than doubled, reaching 17.35 micrograms of protein per milligram of microspheres, and release kinetics shifted from an early burst to a sustained drip extending beyond three weeks.

The complete system assembles these elements into an injectable composite. Vesicle-loaded, polydopamine-coated microspheres are suspended in a hybrid hydrogel combining the decellularized adipose matrix with the crosslinkable hyaluronic acid derivative. The formulation flows smoothly through a needle with an inner diameter of just 250 micrometers, then sets rapidly under ultraviolet light followed by thermal gelation at body temperature. Rheological testing confirmed the material’s viscosity and elastic properties are suitable for precise placement at target anatomical sites. In laboratory co-cultures, hydrogels loaded with the mechanically derived vesicles again outperformed all controls, driving fat differentiation, endothelial tube formation, and cell migration.

The decisive test came in living animals. Thirty-six nude mice received subcutaneous injections of four hydrogel formulations: with empty uncoated microspheres, with empty coated microspheres, with chemically derived vesicles, or with mechanically derived vesicles. Over eight weeks, all grafts shrank, as implanted materials invariably do, but the degree of loss told a striking story. Grafts without vesicles retained only about 36 to 40 percent of their original volume, while both vesicle-loaded formulations preserved roughly 55 to 57 percent. Histological examination showed no necrosis, infection, or rejection in any group, and the vesicle-containing grafts filled with perilipin-positive fat cells bearing the large, single lipid droplets characteristic of mature adipocytes.

Blood vessel formation followed a similar pattern. Grafts carrying mechanically derived vesicles displayed abundant CD31-positive vascular structures at every time point, following a biphasic course in which dense networks of small vessels formed early and then matured into a moderate, stable density. Immunofluorescence and gene expression analysis confirmed that the vesicle-loaded grafts, particularly those with mechanically derived particles, showed elevated levels of adipogenic regulators including PPAR-gamma, CEBP-alpha, and FABP-4 throughout the observation period, while empty-microsphere controls lagged far behind.

To explain why the mechanically derived vesicles worked better, the researchers sequenced their microRNA cargo. The two vesicle populations carried distinct profiles, with 752 microRNAs detected in the mechanically derived particles versus 394 in the chemically derived ones, and only 325 shared species. Among the microRNAs significantly enriched in the superior particles was miR-143, a molecule previously linked to enhanced fat cell formation and blood vessel growth through suppression of the MAPK signaling pathway. Western blot analysis of the grafts confirmed the prediction: phosphorylation of the key MAPK kinases ERK, JNK, and p38 was reduced in grafts receiving mechanically derived vesicles, consistent with miR-143-mediated pathway inhibition steering cells toward fat differentiation.

The work represents a conceptual shift in how scientists approach extracellular matrix biomaterials. Rather than treating decellularized scaffolds as opaque black boxes of biological signals, the study isolates the specific nanoscale effectors responsible for regeneration and delivers them in a controlled, sustained fashion. The authors caution that important hurdles remain: vesicle isolation is time-consuming and resource-intensive, the microspheres had not fully degraded by the end of the eight-week study, and the system has so far been tested only in healthy animals rather than in compromised tissue environments such as diabetic or irradiated wounds. Direct functional validation of miR-143’s role is also still needed. Even so, the demonstration that processing method determines both the yield and the potency of matrix-bound nanovesicles, and that a microsphere-hydrogel composite can exploit them to build vascularized fat tissue, points toward a future in which soft tissue reconstruction relies not on what surgeons can transplant, but on what biomaterials can be instructed to grow.

Subject of Research: Sustained delivery of adipose matrix-bound nanovesicles via microsphere-loaded hybrid hydrogels for adipose tissue engineering

Article Title: An injectable microsphere-reinforced system for sustained delivery of Adipo-MBV in adipose tissue engineering

Article References: Xu, M., Chen, J., Sun, Y., Yang, H., Ji, H., Xu, T., Lu, F., & He, Y. (2026). An injectable microsphere-reinforced system for sustained delivery of Adipo-MBV in adipose tissue engineering. Journal of Advanced Research, 88, 977-994. https://doi.org/10.1016/j.jare.2026.01.058

Image Credits: AI Generated

DOI: Not provided

Keywords: adipose tissue engineering, matrix-bound nanovesicles, extracellular matrix, hyaluronic acid hydrogel, microspheres, polydopamine, drug delivery, adipogenesis, angiogenesis, miR-143, MAPK pathway, regenerative medicine

Pilocytic astrocytoma is a WHO grade 1 glioma, a tumor class that behaves far more indolently than the aggressive glioblastomas that dominate public awareness of brain cancer. These tumors are driven largely by alterations in the MAPK signaling pathway and, in children, are often cured by surgery alone. In adults, however, the disease is less well characterized. Adult tumors tend to arise in different locations, may be less amenable to complete resection, and can recur years or even decades after an initial operation. When they sit in the brainstem, the optic pathway, the hypothalamus, or deep midline ventricular structures, the risk of repeated surgery becomes unacceptable, leaving radiotherapy as the principal local option.

The Heidelberg team, led by Fabian J. K. Allmendinger and colleagues, assembled a retrospective cohort of fourteen adults treated with intensity-modulated proton radiotherapy between 2011 and 2025. The patients were young, with a median age of 23.5 years at treatment, and their tumors occupied some of the most anatomically treacherous territory in the brain: the cerebellum, the frontal and temporal lobes, the third and fourth ventricles, the suprasellar compartment, the mesencephalon, and the pineal region. Ten of the fourteen had undergone prior surgery, and in nine of those cases the operation had achieved only subtotal removal. For ten patients, proton therapy was salvage treatment for recurrent disease; for four, it was the primary local therapy when surgery was judged too risky.

The technical premise of proton therapy is elegantly simple. Unlike conventional photon beams, which deposit radiation along their entire path through tissue and exit on the far side of the target, protons carry a finite range. They release most of their energy in a sharply defined burst, the Bragg peak, at a depth determined by their initial energy, and deliver essentially nothing beyond it. By scanning pencil-thin proton beams across the tumor volume, clinicians can conform the dose to irregular targets while dramatically reducing the radiation bath received by uninvolved brain, the temporal lobes, the hippocampi, the optic apparatus, the hypothalamic-pituitary axis, and cerebral blood vessels. For patients expected to live for decades, that reduction in integral dose is not a cosmetic advantage; it is the difference between preserving and progressively eroding neurocognitive, endocrine, and visual function over a lifetime.

The prescribed dose in the cohort was a median of 54.0 Gy(RBE), delivered in roughly 29 fractions, with planning that co-registered treatment CT scans with contrast-enhanced T1-weighted and T2/FLAIR MRI and applied QUANTEC-based constraints for organs at risk. What followed was, by the standards of brain tumor therapy, remarkable. At last follow-up, bidirectional T2-weighted tumor measurements showed complete regression in three patients, partial response of at least fifty percent in seven, and a minor response in two. Only two patients experienced progressive disease. Perhaps most intriguingly, shrinkage frequently continued beyond the twelve-month landmark: ten of the twelve non-progressive patients kept improving after the standardized one-year assessment, a pattern consistent with the slow growth kinetics of grade 1 tumors and a warning against prematurely declaring treatment failure.

Survival outcomes matched the radiographic enthusiasm. Estimated overall survival was one hundred percent at both three and five years, with no deaths recorded within the first five years after therapy. Progression-free survival stood at 83.3 percent at both timepoints, and most progression events occurred early, meaning that patients who remained disease-free in the initial years tended to stay that way. Median clinical follow-up extended to nearly ten years, with vital status confirmed through national registry data, lending unusual depth to the survival analysis for a cohort of this size.

Toxicity was predominantly low grade. During treatment, the most common acute effects were focal alopecia in 64 percent of patients, fatigue and headache in 43 percent each, and radiodermatitis in 29 percent, and nearly all of these resolved in follow-up. Alopecia and skin reactions vanished entirely beyond the first months. Fatigue was the most persistent complaint, affecting three patients across all follow-up intervals, while mild cognitive impairment appeared in two. One patient with pre-existing postoperative visual deficits developed late grade 1 visual impairment, though optic nerve dose constraints had been met and imaging showed no optic neuropathy. Critically, no grade 4 or grade 5 events occurred at any point.

The study also shines a light on a subtle diagnostic trap known as radiation-induced contrast enhancement, or RICE. Within months to years after proton therapy, new areas of contrast uptake can appear on MRI within or near the irradiated volume, mimicking tumor progression on a scan. In this cohort, three patients developed RICE, yielding a three- and five-year RICE-free probability of 76.2 percent, with all events occurring in the early post-treatment period. One patient was initially misclassified as having progressed and was started on temozolomide chemotherapy, which had to be abandoned after a single cycle due to blood toxicity; retrospective review showed the enhancing lesion was radiation injury, not tumor, and bevacizumab sufficed. The authors emphasize that distinguishing RICE from true progression, using imaging morphology, temporal evolution, spatial relation to the dose distribution, and clinical course, is essential to avoid unnecessary chemotherapy in patients who otherwise face decades of life.

The findings arrive amid an evolving treatment landscape. Current EANO-EURACAN-SNO guidelines recommend maximal safe resection when feasible, with molecular testing for BRAF and MAPK alterations, and acknowledge reoperation, radiotherapy, and targeted agents such as BRAF and MEK inhibitors as options for recurrent or unresectable tumors. Recent multicenter data show chemotherapy with temozolomide achieves a median progression-free survival of only about twenty months in adult pilocytic astrocytoma, a figure that looks modest against the durable control seen here. The Heidelberg authors are careful, however, not to overreach: the study was retrospective, involved only fourteen patients, lacked a photon comparator, and carried incomplete molecular annotation, so it cannot prove that protons outperform photons, only that they deliver excellent control with acceptable morbidity in a selected, anatomically complex population.

Even with those caveats, the message for patients and clinicians is consequential. For adults facing a progressive pilocytic astrocytoma that surgery cannot safely reach, proton radiotherapy now has dedicated, adult-specific evidence behind it: near-universal radiographic response, complete five-year survival, and side effects that were mostly transient and mild. Because prospective trials are unlikely in a disease this rare, single-center cohorts like this one carry disproportionate weight. The study also reinforces a broader principle of modern radiation oncology, that in long-surviving patients with benign-behaving tumors, the true measure of a treatment is not only whether it controls the disease, but what quality of brain, and of life, it leaves behind ten, twenty, and thirty years later.

Subject of Research: Proton radiotherapy for progressive or surgically unfavorable adult pilocytic astrocytoma

Article Title: Efficacy and safety of proton radiotherapy for progressive or surgically unfavorable adult pilocytic astrocytoma: a single-center experience

Article References: Allmendinger, F. J. K., Cherniienko, Y., Lischalk, J., Walter, J., Mose, L., Wickert, R., Deng, M., Regnery, S., Wessel, L., Kozyra, K., Tessonnier, T., Krieg, S., Debus, J., König, L., & Adena-Eichkorn, T. (2026). Efficacy and safety of proton radiotherapy for progressive or surgically unfavorable adult pilocytic astrocytoma: a single-center experience. Journal of Neuro-Oncology, 179(3), Article 89. https://doi.org/10.1007/s11060-026-05798-8

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05798-8

Keywords: proton radiotherapy, pilocytic astrocytoma, adult glioma, radiation oncology, RICE, tumor control, low-grade glioma, Bragg peak, neuro-oncology, radiation toxicity, MAPK pathway, brain tumors

NF1 is caused by pathogenic variants in the NF1 gene, an unusually large gene located on chromosome 17 that carries the instructions for neurofibromin, a protein widely described as a tumor suppressor. Neurofibromin’s principal job is to act as a brake on cellular growth signaling, specifically by accelerating the conversion of the RAS protein from its active to its inactive state, thereby dampening the mitogen-activated protein kinase, or MAPK, pathway. When that brake fails, cells in nerve sheaths, skin pigment systems, bone, and brain can proliferate abnormally, producing the diverse constellation of features clinicians recognize: café-au-lait macules, freckling in skin folds, Lisch nodules in the iris, skeletal abnormalities, learning difficulties, and an elevated risk of benign and malignant tumors.

The Shanghai cohort offered an unusually rich window into that complexity. Every child in the study underwent genetic testing, and researchers painstakingly curated both the genetic and phenotypic data, using SPSS, GraphPad Prism, and Python for statistical analysis and generating growth curves and variant distribution maps from the integrated dataset. What emerged was a picture of remarkable heterogeneity: patients exhibited a broad range of multisystem manifestations, with skeletal abnormalities and developmental or intellectual impairments standing out as particularly common and as features showing notable differences between the sexes.

Among the most consequential findings is the study’s contribution to understanding growth in children with NF1. Males in the cohort had significantly lower height standard deviation scores than females, and when the team constructed P50, or median, growth curves for their patients, those curves sat consistently below the reference values for healthy children of the same population. This is not a trivial statistical curiosity. Height assessment is one of the most routine measurements in pediatrics, and for children with NF1 it has long been a source of uncertainty: is a child simply short for their family, or is the disorder itself reshaping their growth trajectory?

The new sex-specific growth curves directly address that uncertainty. By incorporating longitudinal growth data from childhood into the analysis, the researchers built a precise reference standard tailored to children with NF1, giving clinicians a benchmark against which growth abnormalities can be evaluated with far more confidence than was previously possible. Earlier studies have established that height impairment in NF1 is characterized by decreased pubertal growth velocity in both sexes, and growth hormone deficiency has been documented in some patients even without suprasellar brain lesions, but the field has lacked contemporary, population-matched charts of the kind this cohort now provides. The implications run in both directions: clinicians will be better able to identify children whose growth deviates even from the NF1-specific curve, signaling a possible endocrine complication that warrants investigation, while also sparing families unnecessary anxiety when a child is tracking appropriately along the disorder’s own, slightly lower, trajectory.

On the genetic side, the study’s findings illuminate how different classes of NF1 variants translate into different clinical realities. Truncating variants, which introduce premature stop signals and typically render the neurofibromin protein nonfunctional, were the most common mutation type in the cohort, accounting for 60.8 percent of cases. But the correlations the researchers uncovered went beyond simple frequency counts. Patients harboring single amino acid variations, in which one building block of the protein is swapped for another without truncating it, exhibited a significantly higher prevalence of short stature than patients with truncating variants. This counterintuitive result, in which a seemingly milder molecular defect produces a more pronounced growth phenotype, echoes prior reports of specific missense mutations affecting the p.Arg1809 residue being associated with Noonan syndrome features, including short stature and pulmonic stenosis, and suggests that altered, rather than simply absent, neurofibromin function may perturb growth signaling in distinctive ways.

Splice variants, which disrupt the precise editing of the gene’s messenger RNA, told a different story. In this cohort, splice variants were associated with unidentified bright objects, known as UBOs, the mysterious hyperintense spots that appear on brain MRI scans of many children with NF1 and have been linked in prior neuroimaging natural history studies to clinical features, and with abnormalities of the optic nerve, the structure most vulnerable to optic pathway gliomas, low-grade tumors that are among the most feared complications of pediatric NF1. If confirmed in larger and more diverse populations, such associations could eventually guide surveillance strategies, allowing clinicians to prioritize MRI screening or ophthalmologic monitoring for children whose genetic test results fall into higher-risk variant classes.

The cohort’s genetic architecture also yielded fundamental insights into how NF1 enters a family in the first place. Among the 229 patients for whom the parental origin of the variant was known, a striking 77.29 percent carried de novo variants, meaning the mutation arose spontaneously in the child rather than being inherited from a parent. This high proportion of fresh mutations is consistent with NF1’s status as one of the classic de novo mutation disorders in human genetics, and it carries real counseling weight: parents of a child with a confirmed de novo variant face a low recurrence risk in future pregnancies, whereas an inherited variant implies a one-in-two risk for each subsequent child. The study also expanded the known variant landscape, identifying 37 novel NF1 variants not previously cataloged, adding to the growing global database that underpins accurate molecular diagnosis. The processed genotype and phenotype data, with patient information anonymized, have been made publicly available on GitHub, reflecting a growing commitment to open data in rare disease research, although raw sequencing data remain restricted by institutional and ethical privacy protections.

The broader significance of the work lies in how it reframes NF1 as a disorder whose clinical course can, at least in part, be read from its genetic code. Revised international diagnostic criteria, published in 2021, now allow a molecular diagnosis of NF1 even in young children who have not yet developed enough clinical features to meet the classic criteria, making genetic testing an increasingly front-line tool. Studies like this one, conducted over more than a decade at a single center with consistent methodology, provide exactly the kind of large, internally coherent evidence base that such testing depends on. They also lay groundwork for the next therapeutic chapter: with MEK inhibitors already transforming the treatment landscape for inoperable NF1-related plexiform neurofibromas, a deeper understanding of how specific variant classes drive specific downstream pathways may eventually inform which patients benefit most from which targeted agents.

Challenges remain, as the researchers themselves acknowledge through the careful framing of their conclusions. Single-center cohorts, however large, reflect one population and one clinical referral pattern, and genotype-phenotype correlations in NF1 are probabilistic rather than deterministic; even within a single variant class, two children can follow dramatically different courses. Modifier genes, stochastic developmental events, and environmental factors all likely contribute to the variability that makes NF1 so difficult to predict. Yet the Shanghai study moves the field measurably forward. It documents, in 301 children followed across 12 years, the breadth of the disorder’s multisystem phenotype; it quantifies sex-related differences in skeletal and neurodevelopmental features; it delivers the first sex-specific growth references built from contemporary childhood data; and it ties variant classes to growth failure, brain imaging findings, and optic nerve abnormalities with statistical rigor. For the families of the estimated one in every 2,500 to 3,000 children born with NF1 worldwide, and for the clinicians who care for them, the message is one of cautious optimism: the era of precisely mapping this unpredictable disease, and of using that map to anticipate and treat its complications, is gathering speed.

Subject of Research: Genotype-phenotype correlations and growth characteristics in pediatric neurofibromatosis type 1

Article Title: Phenotypic and genotypic characteristics of pediatric patients with neurofibromatosis type 1: a 12-year single-center cohort study

Article References: Li, Z.-Y., Li, X., Wen, T., Feng, B.-Y., Song, Y., Hu, J.-Y., Yu, T.-T., Yao, R.-E., & Wang, X.-M. (2026). Phenotypic and genotypic characteristics of pediatric patients with neurofibromatosis type 1: a 12-year single-center cohort study. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01092-9

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01092-9

Keywords: neurofibromatosis type 1, NF1 gene, genotype-phenotype correlation, pediatric genetics, short stature, growth charts, de novo variants, truncating variants, splice variants, optic pathway glioma, neurofibromin, MAPK pathway

The investigation began with an unbiased metabolomic survey of mice with chemically induced colitis. Rather than confirming the team’s expectations, the data pointed somewhere unexpected: levels of pantothenate, the vitamin B5-derived precursor of coenzyme A, were markedly elevated in both the colon and serum of colitic animals. Because pantothenate must be phosphorylated by pantothenate kinases, known as PANK enzymes, before it can enter the coenzyme A biosynthetic pathway, its accumulation signaled that the pathway itself was stalled. Of the three PANK isoforms present in the colon, one stood out. PANK3, the dominant intestinal form, was dramatically reduced at both the messenger RNA and protein levels in colitic mice, and the drop was confirmed by immunohistochemical staining of the colonic epithelium.

The downregulation was not merely a rodent curiosity. Analyzing gene expression datasets from human intestinal biopsies, the researchers found PANK3 significantly decreased in patients with active Crohn’s disease and active ulcerative colitis compared with inactive disease and healthy controls. Tissue staining of patient biopsies from Jiangsu Province Hospital corroborated the finding, showing diminished PANK3 specifically within the intestinal epithelium. When human colon epithelial cell lines were exposed to the inflammatory cytokines TNF-alpha and IFN-gamma, PANK3 levels fell again, replicating in a dish what had been observed in diseased tissue. Taken together, the evidence positioned epithelial PANK3 deficiency as a consistent pathological feature of inflammatory bowel disease across species.

To determine whether the loss of PANK3 actually drives barrier failure rather than simply accompanying it, the team deployed a combination of pharmacological and genetic tools. In cultured epithelial cells subjected to inflammatory challenge, a small-molecule PANK3 agonist called PZ-2891 boosted the expression of intercellular junctional proteins, while Hopantenate, a competitive PANK inhibitor, worsened their decline. In Caco-2 monolayer models, transepithelial electrical resistance and paracellular permeability assays showed that activating PANK3 restored barrier function while blocking it deepened the damage. Directly overexpressing PANK3 in HT29 and NCM460 cells rescued inflammation-induced barrier injury, whereas silencing the gene produced the opposite effect, confirming the relationship in both directions.

In living animals the results were even more striking. Mice engineered to overexpress PANK3 specifically in the intestine via adeno-associated virus were markedly protected against DSS-induced colitis, exhibiting less weight loss, shorter reduction in colon length, preserved crypt architecture, maintained goblet cell populations and reduced inflammatory infiltration. Serum FITC-dextran assays demonstrated tighter barrier integrity, and transmission electron microscopy revealed that shortened microvilli and disrupted apical junction complexes were structurally repaired in the PANK3-overexpressing animals. Conversely, intestinal PANK3 knockdown exacerbated every measure of disease severity and barrier breakdown, establishing PANK3 as a necessary guardian of the epithelial lining during colonic inflammation.

The mechanism connecting a metabolic enzyme to such profound structural changes emerged from transcriptomic profiling. PANK3 overexpression suppressed gene clusters encoding proinflammatory cytokines, extracellular matrix components and drivers of epithelial-to-mesenchymal transition, or EMT, a developmental program in which epithelial cells lose their junctions and polarity and take on migratory, mesenchymal characteristics. In chronic inflammation, pathological persistence of EMT dismantles tight junctions and adherens junctions, degrades the basement membrane and promotes fibrotic remodeling, a signature observed in clinical IBD mucosal samples and correlated with disease severity and therapeutic resistance. PANK3, the study found, acts as a powerful brake on this process, downregulating mesenchymal markers such as vimentin and N-cadherin, suppressing the EMT-driving transcription factors Snail and Twist, and preserving junctional proteins including ZO-1, E-cadherin, occludin and claudins.

Gene set enrichment analysis revealed that the EMT-suppressing effects of PANK3 operated through inhibition of the PI3K/AKT and MAPK signaling pathways, both well-established inducers of the transition. Phosphorylation of PI3K, AKT and ERK fell sharply in PANK3-overexpressing mice and rose in knockdown animals, indicating the enzyme’s influence extended deep into canonical signal transduction. The critical mediator proved to be coenzyme A itself. Quantitative LC-MS/MS measurements showed that PANK3 overexpression significantly increased colonic free CoA abundance while knockdown depleted it, and supplying exogenous CoA to cultured epithelial cells was sufficient to suppress inflammation-induced EMT and downstream signaling. When pantothenate was completely removed from the culture medium, the barrier protection conferred by PANK3 agonism or overexpression was largely abolished, confirming that the enzyme’s benefit depends on the raw material for CoA synthesis.

Having established what PANK3 does, the team turned to why it disappears during colitis. Screening transcription factor prediction databases against the Pank3 promoter uncovered c-Myc, the notorious proto-oncogene, as the prime candidate. c-Myc was significantly upregulated in the colonic lesions of ulcerative colitis patients and in multiple experimental colitis models, and chromatin immunoprecipitation confirmed that c-Myc binds directly to three sites in the Pank3 promoter region. A dual-luciferase reporter assay demonstrated that c-Myc overexpression dramatically represses Pank3 promoter activity, and pharmacological inhibition of c-Myc with the inhibitor 10058-F4 restored PANK3 expression in a dose-dependent manner in cells. In mice, c-Myc inhibition ameliorated DSS-induced colitis, rescued PANK3 levels and improved barrier integrity, establishing a clear c-Myc-PANK3-EMT axis in which inflammation-driven c-Myc overexpression silences PANK3, depletes coenzyme A, permits EMT and dismantles the epithelial barrier.

Perhaps the most clinically tantalizing finding came from a high-throughput virtual screen for PANK3 agonists, which identified folic acid, a widely available and inexpensive B vitamin, as the top candidate. Molecular docking predicted binding to key residues including Lys24, Ser192, Arg207, Val268, Asn299 and Trp341, and a cellular thermal shift assay confirmed that folic acid directly stabilizes the PANK3 protein. Oral folic acid at 30 milligrams per kilogram significantly ameliorated DSS-induced colitis in mice, restoring body weight, colon length, crypt architecture and goblet cell populations while elevating colonic coenzyme A levels. Electron microscopy showed repaired microvilli and restored apical junction complexes, junctional proteins were upregulated, EMT markers and matrix metalloproteinases declined, and PI3K/AKT and MAPK activation was suppressed. Crucially, the protection vanished when PANK3 was knocked down, demonstrating that folic acid’s benefit is PANK3-dependent.

The findings carry substantial implications beyond the immediate identification of a druggable target. A meta-analysis cited in the study indicates that higher folate levels are associated with reduced risk of inflammatory bowel disease, lending clinical plausibility to the mechanistic work, although the therapeutic doses used in mice exceed typical supplementation levels and would likely require colon-targeted formulations such as enteric-coated tablets to maximize local exposure while limiting systemic dose. The authors also suggest that circulating pantothenate and coenzyme A levels, together with intestinal PANK3 expression, could serve as accessible biomarkers for diagnosis and treatment monitoring, pending validation in larger multi-center cohorts. Because reduced PANK3 has previously been identified as a diagnostic marker for early-stage colorectal cancer, and c-Myc is a well-established oncogene, the axis also offers a plausible mechanistic thread connecting chronic colitis to malignant transformation. Open questions remain, including precisely how PANK3-derived coenzyme A suppresses the PI3K/AKT and MAPK pathways, whether coenzyme A acts through post-translational modifications such as protein CoAlation, and whether PANK3 possesses non-catalytic functions. Even so, the study reframes ulcerative colitis in part as a metabolic disease of the epithelial barrier and positions PANK3 agonism, potentially through a humble vitamin, as a promising avenue for restoring the gut’s broken wall.

Subject of Research: Metabolic regulation of intestinal epithelial barrier integrity by the c-Myc-PANK3-coenzyme A axis in ulcerative colitis.

Article Title: c-Myc-PANK3-EMT axis regulates the structure and function of intestinal barrier in ulcerative colitis

Article References: Zhang, S., Chen, Y., Aa, N., Xu, C., Xie, T., Wang, Y., Cheng, T., Wang, M., Yu, H., Ji, X., Zhao, S., Wang, Y., Xiao, J., Xie, Y., Wang, G., & Aa, J. (2026). c-Myc-PANK3-EMT axis regulates the structure and function of intestinal barrier in ulcerative colitis. Journal of Advanced Research, 87, 931-946. https://doi.org/10.1016/j.jare.2025.12.007

Image Credits: AI Generated

DOI: 10.1016/j.jare.2025.12.007

Keywords: ulcerative colitis, PANK3, c-Myc, coenzyme A, epithelial-mesenchymal transition, intestinal barrier, folic acid, pantothenate kinase, inflammatory bowel disease, PI3K/AKT pathway, MAPK pathway, tight junctions