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