The regional burden appears closely tied to diet and socioeconomic conditions. Vitamin B12 is found almost exclusively in animal-source foods and is largely absent from unfortified plant foods, placing women who follow vegetarian or vegan diets at increased risk when animal-source foods are unaffordable. Limited dietary diversity, recurrent gastrointestinal infections that may impair absorption, and low awareness among patients and health workers may compound the problem. Population surveys reinforce the possibility that deficiency begins before pregnancy: among non-pregnant women of reproductive age, 57.7% in rural Haryana and 48.3% in southern India were deficient, while further substantial proportions had marginal concentrations.

Pregnancy itself raises the challenge. Maternal blood concentrations can fall by approximately 10% to 30% as plasma volume expands, while fetal growth, placental transfer and increased maternal red-cell production increase requirements. Reference intervals derived from non-pregnant adults may therefore underestimate depletion. Diagnosis also depends on the marker used. Total serum vitamin B12 is widely available but measures circulating rather than tissue vitamin B12 and can miss functional deficiency. Holotranscobalamin, the fraction bound to transport proteins, can decline earlier, while methylmalonic acid can indicate impaired intracellular function; however, none has a universally validated pregnancy-specific threshold, and methylmalonic acid may also rise with renal impairment.

The clinical associations are broad. Low maternal vitamin B12 and elevated homocysteine have been linked to anemia, pregnancy loss, preeclampsia, gestational diabetes, fetal growth restriction, low birth weight and preterm birth. In a meta-analysis of 10 observational studies involving 10,595 pregnant women, vitamin B12 deficiency was associated with gestational diabetes with an odds ratio of 1.46 and a 95% confidence interval of 1.21 to 1.79. A separate synthesis found that deficiency in the second or third trimester was associated with a higher risk, with an odds ratio of 1.59, and that the association was stronger in Asian populations, with an odds ratio of 2.08. The same analysis linked a high folate-to-vitamin B12 ratio to gestational diabetes, with an odds ratio of 1.87.

Not every outcome or population shows the same relationship, however. Individual-participant data from 18 longitudinal studies found a modest association between maternal deficiency and low birth weight, with an adjusted risk ratio of 1.15 and a 95% confidence interval of 1.01 to 1.31, as well as a consistent association between higher vitamin B12 concentrations and lower preterm-birth risk. Yet the urban MAASTHI cohort in Bengaluru associated low birth weight with vitamin B6 deficiency and impaired folate status rather than vitamin B12 deficiency, and an Irish cohort found no relationship between dietary vitamin B12 and fetal growth, placental weight or birth weight. These discordant results show that circulating vitamin B12 may sometimes mark broader dietary, socioeconomic or metabolic conditions rather than act as an independent cause.

The review also links low maternal status to congenital anomalies and later development. A meta-analysis of 38 case-control studies found lower maternal vitamin B12 in pregnancies affected by neural tube defects, with a standardized mean difference of -0.23 and a 95% confidence interval of -0.32 to -0.14; the association persisted in analyses where folate levels did not differ. Small studies have also associated low maternal vitamin B12 with orofacial clefts and, in Bangladeshi pregnant women, with oligohydramnios, fetal hydrocephalus and neural tube defects. Offspring neurodevelopment is more difficult to assess. Observational cohorts and small interventions suggest possible differences in language, cognition and motor development, but a scoping review of 19 studies involving 23,825 mothers and children judged the overall evidence inconclusive.

Randomized trials provide the clearest answer about treatment, and their main consistent effect is biochemical rather than clinical. A Cochrane review of five trials involving 984 pregnant women found that supplementation increased maternal vitamin B12 concentrations by 60.89 picomoles per liter on average, with a 95% confidence interval of 40.86 to 80.92, and reduced the risk of maternal deficiency, with a risk ratio of 0.38. The certainty of this evidence was rated very low, and clinical benefits for mothers and children remained uncertain. Trials in Bangladesh also reported improvements in breast-milk and infant vitamin B12 status, lower methylmalonic acid and changes in immune or oxidative-stress markers, but these findings do not establish prevention of pregnancy complications.

The multicentre MATCOBIND trial illustrates both the promise and the limits of intervention research. It randomized 708 predominantly vegetarian women in India and Nepal, of whom 531 completed follow-up. Participants received either 250 micrograms of methylcobalamin daily or 50 micrograms as an active comparator from the first trimester until six months after delivery. The higher dose produced larger improvements in maternal and infant vitamin B12 status and was associated with a roughly two-point improvement in infant mental developmental quotient at nine to 12 months, but not in motor development. A large Nepalese trial likewise improved maternal status without detecting differences in infant length or cognitive development at 12 months. These results are preliminary because MATCOBIND was a single trial with short follow-up and an active comparator rather than a placebo, and its neurodevelopmental findings have not yet been independently replicated.

Mechanistic evidence offers a possible explanation for the associations while reinforcing the need for caution. Vitamin B12 is required for remethylation of homocysteine to methionine, linking it to folate-dependent one-carbon metabolism and the production of methyl donors. Deficiency can create a functional folate trap, potentially limiting nucleotide synthesis in rapidly dividing blood, placental and embryonic tissues. Accumulated homocysteine may also contribute to oxidative stress, reduced nitric oxide availability and endothelial dysfunction, while changes in DNA and histone methylation could affect fetal development. These pathways are biologically plausible, but the direction, persistence and clinical importance of epigenetic changes remain uncertain, and homocysteine may be a marker of disrupted metabolism rather than its sole mediator.

The low-vitamin B12, high-folate imbalance is especially relevant because India’s national antenatal programme supplies iron and folic acid but not vitamin B12. Observational studies associate this pattern with gestational diabetes, small-for-gestational-age infants and childhood insulin resistance, including in the Pune Maternal Nutrition Study, but the evidence does not justify withdrawing folic acid. Indeed, some analyses attribute elevated gestational-diabetes risk to high red-blood-cell folate independently of vitamin B12, and lower folate concentrations have predicted progression from pregnancy-induced hypertension to preeclampsia in one large cohort. The review therefore concludes that current evidence supports identifying and treating confirmed deficiency, particularly among women with vegetarian or vegan diets, low dietary diversity, socioeconomic disadvantage, suggestive clinical features or relevant pregnancy histories, while maintaining folic acid provision. It finds that the evidence remains insufficient for universal vitamin B12 supplementation across all pregnancies. Priorities are pregnancy-specific diagnostic thresholds, independently replicated trials beginning around conception and continuing into childhood, and cost-effectiveness studies of risk-based screening in South Asian antenatal care.

Subject of Research: Maternal vitamin B12 deficiency, pregnancy outcomes and antenatal care in South Asia

Article Title: Maternal vitamin B12 deficiency in pregnancy: burden, associated outcomes, and implications for antenatal care in South Asia—a narrative review

Article References: Yadav, A., Gandhi, K. Y., & Puri, M. (2026). Maternal vitamin B12 deficiency in pregnancy: burden, associated outcomes, and implications for antenatal care in South Asia—a narrative review. Frontiers in Nutrition, 13, 1896162. https://doi.org/10.3389/fnut.2026.1896162

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1896162

Keywords: vitamin B12 deficiency, pregnancy, South Asia, antenatal care, folic acid, one-carbon metabolism, gestational diabetes, neural tube defects, offspring neurodevelopment, supplementation, Maternal, vitamin

The study under discussion approached this question by combining several complementary analytical strategies, each of which addresses a different limitation of conventional observational research. Observational studies of psoriasis and depression are notoriously vulnerable to confounding: shared risk factors such as obesity, smoking, alcohol use, sleep disturbance, and socioeconomic adversity influence both conditions independently, making it difficult to determine whether the association reflects causation or shared predisposition. Mendelian randomization offers a way around this obstacle by exploiting the random allocation of genetic variants at conception. Because alleles are inherited independently of environmental exposures and lifestyle factors, genetic variants that influence gene expression can serve as proxies—so-called instrumental variables—for testing whether altered expression of a particular gene causally affects disease risk. When the researchers used expression quantitative trait loci, or eQTLs, from the eQTLGen consortium as instruments, they identified 340 gene-expression signals associated with psoriasis and 307 associated with depression, of which only nine genes showed evidence of causal involvement in both directions. This small intersection is itself informative: it suggests that the molecular overlap between the two disorders is concentrated in a limited set of genes rather than being distributed diffusely across the genome, narrowing the search space for therapeutic targets considerably.

The nine intersecting genes were then subjected to least absolute shrinkage and selection operator regression, a machine learning technique designed to identify the most predictive features from a larger candidate pool while guarding against overfitting. LASSO works by applying a penalty that shrinks the coefficients of less informative variables toward zero, effectively forcing the model to rely on only the most robust predictors. From this procedure, four genes emerged as central hubs: MAP3K20, WARS2, TBXAS1, and ABHD15. Each of these genes carries a distinct biological profile that helps explain how a skin-limited inflammatory disease and a neuropsychiatric condition could share common molecular ground.

MAP3K20, better known in the literature as ASK1, encodes a mitogen-activated protein kinase kinase kinase that sits at a critical junction in cellular stress signaling. It activates the p38 and JNK pathways in response to oxidative stress, endoplasmic reticulum stress, and inflammatory cytokines such as tumor necrosis factor-alpha. In the context of psoriasis, MAP3K20 signaling in keratinocytes contributes to the proliferative and pro-inflammatory responses that characterize plaque formation. In neural tissue, the same pathway has been implicated in stress-induced neuronal dysfunction and in the neuroinflammatory responses associated with depressive-like behavior in animal models. The dual role of MAP3K20 in both epithelial inflammation and stress-responsive neural signaling makes it a plausible molecular bridge between the two conditions.

WARS2 encodes tryptophanyl-tRNA synthetase, the mitochondrial enzyme responsible for charging transfer RNA molecules with tryptophan during protein synthesis. This gene occupies an intriguing position at the intersection of several pathways relevant to the comorbidity. Tryptophan is not only a building block for proteins but also the precursor for serotonin synthesis, and disruptions in tryptophan availability or metabolism have long been linked to mood disorders. Moreover, tryptophan is diverted along the kynurenine pathway during inflammation, generating neuroactive metabolites that can be either neuroprotective or neurotoxic depending on the enzymatic context. Chronic inflammatory conditions like psoriasis shift tryptophan metabolism toward kynurenine, potentially reducing serotonin availability in the brain while simultaneously producing metabolites that influence glutamate signaling and neuronal survival. A gene that governs tryptophan handling at the cellular level therefore connects inflammatory metabolism directly to monoamine neurotransmission.

TBXAS1 encodes thromboxane A synthase 1, the enzyme that converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and platelet aggregator. Thromboxane signaling is well established in cardiovascular biology, and elevated thromboxane production is a recognized feature of the systemic inflammatory state that accompanies psoriasis and contributes to the elevated cardiovascular risk observed in these patients. Less widely appreciated is the role of thromboxane signaling in the central nervous system, where it influences microglial activation, neurovascular function, and inflammatory signaling within the brain. The presence of TBXAS1 among the shared genes suggests that prostanoid metabolism may represent a conduit through which peripheral inflammatory signals generated in psoriatic skin and vasculature are translated into neuroinflammatory changes relevant to depression.

ABHD15, the least characterized of the four, encodes a protein that functions as a regulator of lipolysis and has been implicated in metabolic signaling pathways. Its identification in this analysis points toward the metabolic dimension of the comorbidity. Psoriasis is strongly associated with metabolic syndrome, insulin resistance, and dyslipidemia, and depression likewise shows consistent associations with altered lipid metabolism and insulin signaling. The enrichment results reported in the study highlighted cholesterol metabolism as one of the pathways in which the four hub genes participate, reinforcing the idea that lipid biology constitutes a shared mechanistic layer between the two disorders.

Pathway enrichment analysis of these four genes revealed convergence on the interleukin-17 signaling cascade, nuclear factor kappa B activation, and FoxO transcription factor regulation. The IL-17 pathway is the signature immune axis of psoriasis, and biologic drugs targeting IL-17 or its receptor have transformed the treatment of moderate to severe disease. NF-kappa B serves as a master transcriptional regulator of inflammatory gene expression across virtually all cell types, integrating signals from cytokine receptors, pattern recognition receptors, and stress pathways into coordinated transcriptional responses. FoxO transcription factors, meanwhile, govern cellular responses to oxidative stress, regulate autophagy, and influence neuronal survival. The convergence of all four hub genes on these pathways suggests that the comorbidity operates through a self-reinforcing circuit in which IL-17-driven inflammation activates NF-kappa B in both peripheral immune cells and central nervous system cells, while FoxO-mediated stress responses determine whether cells succumb to or survive the inflammatory assault.

Perhaps the most novel finding to emerge from the single-cell sequencing component of the analysis was the connection to ferroptosis, a form of regulated cell death discovered relatively recently and defined by its dependence on iron-catalyzed lipid peroxidation. Unlike apoptosis or necroptosis, ferroptosis is driven by oxidative damage to lipid membranes and is suppressed by the glutathione peroxidase 4 enzyme and by system xc-mediated cystine import. Ferroptosis has been implicated in a growing list of inflammatory and neurodegenerative conditions, and its involvement in both psoriatic keratinocytes and depressive neurocircuitry represents an emerging area of investigation. In the skin, ferroptotic death of keratinocytes can release damage-associated molecular patterns that amplify inflammatory signaling, potentially perpetuating the psoriatic cycle. In the brain, ferroptosis of neurons and oligodendrocytes has been linked to the hippocampal atrophy and synaptic dysfunction observed in chronic stress models and in patients with major depression. The correlation between the four hub genes and ferroptosis markers identified in this study suggests that iron-dependent lipid peroxidation may serve as a downstream execution mechanism through which chronic inflammation translates into cellular damage in both organ systems.

The single-cell transcriptomic data added a layer of cellular resolution that bulk RNA sequencing cannot provide. By examining individual cells from psoriatic skin lesions and from brain-related tissue in depression cohorts, the researchers were able to determine which cell populations express the four hub genes and how that expression changes in disease states. This cell-type-specific localization matters because the same gene can perform entirely different functions depending on whether it is expressed in keratinocytes, endothelial cells, infiltrating neutrophils, microglia, or neurons. The finding that the hub genes show enrichment in specific immune cell populations and correlate with patterns of immune infiltration provides a spatial framework for understanding how molecular signals propagate across tissue boundaries.

Turning from mechanism to therapeutics, the researchers queried the Comparative Toxicogenomics Database, a publicly available resource that catalogs interactions between chemicals, genes, and diseases, to identify compounds that might modulate the activity of the four hub genes. Among the candidates that emerged, folic acid stood out for its ability to target three of the four genes. Folic acid, the synthetic form of folate or vitamin B9, is an essential cofactor in one-carbon metabolism, supporting the synthesis of purines, thymidine, and the methyl groups required for epigenetic regulation and neurotransmitter synthesis. Folate deficiency has long been associated with depression, and low folate levels predict poorer response to selective serotonin reuptake inhibitors, which is why L-methylfolate is sometimes used as an adjunctive treatment in psychiatry. In the context of psoriasis, folate metabolism intersects with the rapid keratinocyte proliferation that characterizes the disease, and methotrexate—the most widely used conventional systemic agent for psoriasis—works in part by inhibiting folate-dependent enzymes, which is why folate supplementation is routinely co-prescribed to mitigate toxicity.

The identification of folic acid as a potential modulator of the shared molecular network therefore carries both mechanistic and clinical significance. It suggests that the same nutrient pathway that supports neurotransmitter synthesis in the brain also influences the proliferative and inflammatory programs active in psoriatic skin, providing a biological rationale for why nutritional status might modulate both conditions simultaneously. It also raises the possibility that folate-related interventions, whether through dietary optimization, supplementation, or pharmacological modulation of one-carbon metabolism, could be explored as adjunctive therapies aimed at the comorbidity rather than at either condition in isolation.

It is worth emphasizing what this study does and does not establish. The findings rest on computational integration of publicly available datasets rather than on new laboratory experiments or clinical trials, and the causal inferences drawn from Mendelian randomization depend on assumptions—that the genetic instruments are valid proxies, that they influence the outcomes only through the exposure of interest, and that confounding through population stratification has been adequately controlled. The eQTL data were derived from peripheral blood, which may not fully capture gene expression in skin or brain tissue, and the GWAS summary statistics came from populations of European ancestry, potentially limiting generalizability to other populations. The sample sizes for the psoriasis transcriptomic datasets were modest, and single-cell datasets, while informative, reflect specific tissue contexts that may not represent the full cellular diversity of either disease. These limitations do not invalidate the findings but rather frame them as hypothesis-generating results that require experimental validation in cellular models, animal studies, and ultimately prospective clinical cohorts.

Nevertheless, the study contributes a structured framework for thinking about psoriasis and depression as a biologically integrated comorbidity. By triangulating genetic causality, transcriptomic signatures, machine learning feature selection, and single-cell resolution, it narrows a vast molecular landscape down to four genes and a handful of interconnected pathways. The convergence on IL-17 signaling, NF-kappa B activation, FoxO regulation, cholesterol metabolism, synaptic vesicle cycling, and ferroptosis paints a coherent picture in which chronic inflammatory signaling, altered lipid handling, and oxidative stress-induced cell death form a mutually reinforcing network spanning skin, vasculature, and brain. For clinicians, the findings reinforce the importance of routine depression screening in psoriasis care and suggest that monitoring inflammatory markers, metabolic parameters, and nutritional status may provide actionable windows into comorbidity risk. For researchers, the four hub genes and the pathways they anchor offer concrete starting points for experimental validation and for the development of interventions that target the shared biology underlying both conditions, moving the field closer to the goal of precision therapy for patients living with the burden of this dual diagnosis.

Subject of Research: Molecular mechanisms underlying the comorbidity of psoriasis and depression

Article Title: Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing

Article References: De, B., Bao, W., Hea, N., & Fang, J. (2026). Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing. Frontiers in Molecular Medicine, 6, Article 1770665. https://doi.org/10.3389/fmmed.2026.1770665

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1770665

Keywords: psoriasis, depression, Mendelian randomization, single-cell sequencing, transcriptomics, ferroptosis, folic acid, MAP3K20, WARS2, TBXAS1, ABHD15, immune infiltration

To understand why researchers have been drawn to folic acid in the first place, it helps to look at the biology. Vitamin B9 is a central player in one-carbon metabolism, a biochemical network that supplies methyl groups for the synthesis of DNA, the metabolism of amino acids and, crucially, the production and regulation of neurotransmitters in the central nervous system, including monoamines such as serotonin and dopamine that are intimately involved in mood regulation. Folate status has been repeatedly linked to depression, to markers of inflammation and to suicidal behaviour in observational research, and low folate levels have been found in subsets of people with affective disorders. Because the vitamin is inexpensive, widely available, easy to administer and largely free of serious side effects, it has long been considered a biologically plausible candidate for a low-threshold preventive intervention, one that could in principle reach vulnerable people without the stigma, cost and access barriers associated with conventional psychiatric care.

The 2022 JAMA Psychiatry findings seemed to give that plausibility empirical teeth. By linking prescription records to episodes of self-harm in a large American population, the study’s authors reported that months in which patients had folic acid coverage were associated with substantially lower rates of suicide attempts and intentional self-harm. The result generated headlines and, according to the researchers behind the new Swedish work, genuine interest in prescribing folic acid to groups considered at elevated risk. But the study was observational, meaning it measured associations in existing data rather than randomly assigning treatment, and it left open the perennial question that haunts all such research: did the vitamin reduce risk, or were people who happened to receive prescriptions simply different in ways that mattered?

The Swedish team, led by Professor Jussi Jokinen of Karolinska Institutet and Umeå University, set out to test whether the folic acid signal would hold up in a different health system, a different population and a different outcome measure. Rather than tracking suicide attempts, they examined suicide-related deaths among young adults, an age band in which suicide remains a leading cause of mortality. The researchers analysed openly available nationwide data covering the period from 2006 to 2021, encompassing all 21 Swedish regions. Among people aged 20 to 29 years, the dataset included 3,463 suicide-related deaths, of which 2,693 were classified as suicides and 770 as deaths from events of undetermined intent, a category that often includes cases where suicidal intent could not be formally established.

The results, presented by Jokinen together with colleagues A. Mert and A. Desai Boström, did not point in a single direction. Among men aged 20 to 24, higher annual folic acid dispensing rates were associated with a higher concentration of suicide-related deaths, the opposite of what a simple protective story would predict. Yet among men aged 25 to 29, folic acid dispensing was associated with a decrease in suicide-related deaths, echoing the direction of the American findings. Among women, no statistically significant associations emerged at all. This patchwork of divergent, sex- and age-specific patterns is precisely what makes the new study difficult to reconcile with a straightforward causal narrative in which folic acid supplementation uniformly lowers suicide risk.

Jokinen was careful to frame the findings in terms of caution rather than alarm. Our results should not be interpreted as evidence that folic acid increases suicide risk, he said. What they do suggest is caution. Observational associations between prescriptions and suicidal behaviour can be difficult to interpret, because people who receive a treatment may differ in important ways from people who do not. That distinction between association and causation sits at the heart of the debate. The Swedish analysis compared regional dispensing patterns with regional mortality counts rather than following individual people who did or did not take folic acid, an ecological design that can reveal population-level signals but cannot determine whether the vitamin itself affected any single person’s risk.

The researchers highlight one methodological trap in particular: confounding by indication. Folic acid is prescribed for a variety of reasons, from confirmed deficiency and anaemia to supporting treatment of depression, and some of the medical, psychiatric or behavioural circumstances that lead a clinician to recommend supplementation may themselves be linked to suicide risk. In such a scenario, a folic acid prescription may function as an indicator of underlying health circumstances rather than as the cause of the observed outcome. A region or subgroup with more psychiatric morbidity might both dispense more supplements and experience more suicides, producing an apparent association that has nothing to do with the vitamin’s pharmacology. The same logic, running in the opposite direction, could also mask genuine protective effects in some groups. These limitations, the authors emphasise, mean the findings should be read as a signal warranting further investigation, not as evidence for either a beneficial or a harmful causal effect of supplementation.

Jokinen stressed that the Swedish results do not directly contradict the earlier American work, because the populations, outcomes and study designs differ in fundamental ways. Earlier work raised the important possibility that folic acid might be associated with reduced suicidal behaviour, he said. Our study does not directly contradict that work, because the populations, outcomes and study designs are different: it shows that the picture is not straightforward. Before folic acid can be discussed as a suicide-prevention strategy, we need individual-level longitudinal studies that can account for why it was prescribed and for patients’ clinical characteristics. It means the jury is still out. He added that the findings should not prompt any changes in the clinical use of folic acid, and that clinicians and researchers should resist interpreting prescription-outcome associations as proof of a direct protective effect. The key next step, he argued, is individual-level longitudinal research linking folic acid prescriptions to treatment indications, psychiatric and medical diagnoses, other medications, substance use and, ideally, biological folate measures, which would help determine whether the observed associations reflect an effect of the vitamin itself or the characteristics of the patients for whom it is prescribed.

Independent commentators see the study as a useful corrective to premature enthusiasm. Dr Xenia Gonda of Semmelweis University in Budapest, who was not involved in the work, said the findings underline that suicidal behaviour is not a single, biologically uniform phenomenon. Understanding its diverse neurobiological pathways, and how these may differ by sex and age, is essential if we are to identify new, more precisely targeted opportunities for prevention also at the population level, she said, noting that this is particularly important for potential interventions such as folic acid, which is inexpensive, widely available, easy to use and free from the high thresholds and stigma often associated with accessing psychiatric care. At the same time, she cautioned, accessibility and biological plausibility do not establish efficacy, and the authors are right to emphasise that observational findings cannot demonstrate either a causal role for folic acid in the development of suicidal behaviour or a protective effect of supplementation. The observed sex- and age-related differences, she argued, are especially valuable because they highlight the need to move beyond one-size-fits-all models in both suicide research and psychiatric prevention.

For now, the practical takeaway for patients and clinicians is one of continuity rather than change: nothing in the Swedish data justifies altering how folic acid is prescribed, and nothing in it supports adding the vitamin to suicide-prevention protocols on the strength of current evidence. What the study does deliver is a methodological warning shot for the field. Suicide prevention research is crowded with interventions that looked promising in observational data and failed under stricter scrutiny, and the folic acid story now illustrates how the same exposure can produce opposite associations in adjacent subgroups of the same country over the same period. The authors are preparing a manuscript for submission to a peer-reviewed journal, and the work has not yet undergone peer review, so the findings should be treated as preliminary. Until individual-level, longitudinal studies with proper accounting for prescribing indications and clinical characteristics are completed, the question of whether vitamin B9 can meaningfully reduce suicide risk remains, as Jokinen put it, an open one, with the jury still deliberating.

Subject of Research: Association between folic acid supplementation and suicide-related deaths among young adults in Sweden

Article Title: Study questions benefit of folic acid (vitamin B9) supplementation in reducing suicides

Article References: Study questions benefit of folic acid (vitamin B9) supplementation in reducing suicides. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: folic acid, vitamin B9, suicide prevention, suicidal behaviour, observational study, confounding by indication, ECNP Congress, Karolinska Institutet, JAMA Psychiatry, young adults, psychiatry, Sweden

Neural tube defects, which include spina bifida and anencephaly, arise when the embryonic structure that becomes the brain and spinal cord fails to close properly during the first four weeks of development, often before a woman even realizes she is pregnant. Decades of evidence have established that adequate folic acid intake around the time of conception can prevent a large proportion of these defects, which remain a major preventable cause of congenital disability worldwide. Because the window for protection closes so early, public health authorities recommend that women begin taking a daily folic acid supplement before conception and continue through at least the first trimester. The new research set out to determine whether women of childbearing age in mainland China are translating that general message into precise, correctly timed behavior.

The investigation took a mixed-methods approach conducted between June and September 2024. In the quantitative phase, the researchers administered a study-specific questionnaire online to 5,741 women aged 18 to 49 years recruited from different regions of mainland China through a convenience sample. The survey assessed folic acid-related knowledge and supplementation behaviors, and the team used univariable and multivariable logistic regression analyses to examine the association between knowledge scores and correct supplementation. In the qualitative phase, the researchers conducted semi-structured interviews with 18 pregnant women, guided by the Health Belief Model, a well-established psychological framework that explains health behavior through perceptions of susceptibility, severity, benefits, obstacles, and cues to action. Qualitative data were analyzed using directed content analysis, and the quantitative and qualitative findings were integrated through a joint display to reveal where numbers and lived experience converged or diverged.

The headline numbers from the survey reveal a knowledge pyramid that narrows sharply as it descends from general awareness to actionable detail. Among the 5,741 survey participants, 5,490 women, or 95.6 percent, knew that folic acid prevents neural tube defects. But only 3,594, or 62.6 percent, knew the correct timing for supplementation, and just 2,949, or 51.4 percent, knew the recommended daily dose. In other words, while nearly all women had absorbed the core public health message, roughly half were missing the operational specifics that determine whether supplementation actually protects an embryo during the window of neural tube closure.

Behavioral data told an even more sobering story. Among the 4,470 women with pregnancy or pregnancy-planning experience, 3,858, or 86.3 percent, had obtained folic acid, and 3,708, or 83.0 percent, had actually taken it. Yet only 1,281 women, or 28.7 percent, adhered to the full regimen. The steep drop-off between obtaining the supplement and completing the recommended course indicates that the challenge is not access or initial motivation but sustained, correctly timed adherence. A bottle of folic acid purchased after a positive pregnancy test, or abandoned partway through the preconception period, offers far less protection than one taken daily from before conception onward.

The statistical analysis confirmed that knowledge is not merely correlated with good practice by chance. After adjusting for other variables, the researchers found that knowledge scores were significantly associated with adherence to correct supplementation, with an adjusted odds ratio of 1.493 and a 95 percent confidence interval of 1.43 to 1.56. Each increment in knowledge corresponded to meaningfully higher odds of taking folic acid correctly. This dose-response-like relationship between understanding and behavior strengthens the case that the knowledge gaps in timing and dosage are not benign oversights but active contributors to suboptimal supplementation practices.

The qualitative interviews added psychological texture to these statistics. Using the Health Belief Model as an analytical lens, the researchers identified barriers spanning all five of the framework’s core constructs. Women’s decisions were shaped by how susceptible they perceived themselves to be to having an affected pregnancy, how severe they believed the consequences would be, how beneficial they judged supplementation to be, what obstacles they encountered in obtaining and taking the supplement, and what cues prompted them to act. These perceived factors help explain why a woman who knows that folic acid prevents birth defects in the abstract might still fail to start early, take the right dose, or persist through the recommended duration.

When the quantitative and qualitative strands were integrated through the joint display, a coherent picture of the knowledge-practice gap emerged. The researchers concluded that limited knowledge of the recommended timing and dosage, health information that was insufficiently individualized, and brief counseling from healthcare providers may all contribute to suboptimal supplementation practices. Generic advice delivered in passing during a busy prenatal visit appears inadequate to convey the operational precision that folic acid prevention demands. Women need to hear not just that the vitamin matters, but exactly when to begin, how much to take each day, and how long to continue, with that guidance tailored to their circumstances.

The study, which received no external funding and was approved by the Institutional Review Board of the Peking University Biomedical Ethics Committee, carries clear implications for preconception health education in China and beyond. The authors call for preconception health education that provides specific, individualized, and theory-informed guidance on when, how much, and how long folic acid should be taken. Grounding educational interventions in behavioral frameworks such as the Health Belief Model could help address the perceived barriers that interviews uncovered, while longer and more structured provider counseling could close the timing and dosage knowledge gaps that the survey documented.

For a preventable cause of congenital disability, the distance between 95.6 percent awareness and 28.7 percent full adherence represents an enormous unrealized opportunity. The neural tube closes within the first four weeks of embryonic development, meaning that every month of delayed initiation or interrupted adherence translates into real risk. This research demonstrates that closing the gap requires moving beyond slogans about folic acid’s importance and toward communication that equips women with the concrete, actionable details of the regimen. As the authors’ findings make plain, knowing that a supplement prevents birth defects is only the first step; knowing precisely how to take it is what turns knowledge into protection.

Subject of Research: Folic acid supplementation knowledge and adherence for neural tube defect prevention among women of childbearing age in China

Article Title: Discrepancy between knowledge and practice in folic acid supplementation for NTD prevention: a mixed-methods study of Chinese women

Article References: Li, J., Peng, X., He, H., Liu, N., Dong, W., Lv, D., Li, S., & Zhu, X. (2026). Discrepancy between knowledge and practice in folic acid supplementation for NTD prevention: a mixed-methods study of Chinese women. BMC Public Health. https://doi.org/10.1186/s12889-026-29848-y

Image Credits: AI Generated

DOI: 10.1186/s12889-026-29848-y

Keywords: folic acid, neural tube defects, women of childbearing age, medication adherence, health belief model, mixed-methods research, preconception health, public health, China, nutritional supplements, health education, pregnancy planning

The research team, led by investigators at the Aging Research Center of Karolinska Institutet and Stockholm University, set out with a specific and technically ambitious goal. Rather than examining a single disease endpoint, they wanted to identify the blood biomarkers most strongly associated with adherence to several well-established dietary patterns and to describe the pathophysiological domains those markers belong to. To do this, they drew on fifty-four blood biomarkers spanning four major domains: metabolic, inflammatory, vascular, and neurodegenerative. This breadth matters, because aging is not driven by any single pathway. It is the product of interacting processes, from glucose regulation and lipid transport to chronic low-grade inflammation and neural injury, and a diet’s biological fingerprint may be scattered across all of them.

Dietary intake in the study was assessed using validated food frequency questionnaires, the standard instrument for capturing what people eat over extended periods. The researchers then scored diet quality in three complementary ways. The first was adherence to the Alternative Mediterranean Diet, or AMED, a scoring system that rewards high consumption of vegetables, legumes, fruits, nuts, whole grains, fish, and monounsaturated fats, with moderate alcohol intake and limited red and processed meat. The second was the Alternative Healthy Eating Index, or AHEI, a broader index developed to capture foods and nutrients most strongly linked to lower chronic disease risk. The third was a reverse-transformed Empirical Dietary Inflammatory Index, or rEDII, which quantifies the inflammatory potential of the diet; higher rEDII scores in this transformation indicate a less pro-inflammatory, and therefore more favorable, dietary pattern.

On the statistical side, the team used quantile regression to examine cross-sectional associations between dietary adherence and standardized biomarker levels, adjusting for sociodemographic and lifestyle factors. Quantile regression is a technically deliberate choice: by modeling the median of each biomarker distribution rather than only the mean, the approach is less sensitive to extreme values and outliers, which are common in biological data from older populations. The researchers also corrected for multiple comparisons, a safeguard against the false positives that inevitably arise when dozens of biomarkers are tested simultaneously. Associations were expressed per one standard deviation increment in dietary adherence, allowing effects to be compared across different diets and biomarkers on a common scale.

The results were striking in their specificity. Higher adherence to the Mediterranean-style AMED pattern was directly associated with higher blood levels of folic acid, with a beta coefficient of 0.066, and inversely associated with glial fibrillary acidic protein, or GFAP, a marker of astrocyte activation that is increasingly studied as an indicator of neurodegenerative processes in the brain. The inverse association with GFAP, at a coefficient of -0.018, is particularly intriguing because it hints that a Mediterranean-style diet may be linked to a quieter profile of glial activity, the cellular inflammation within the brain that is thought to accompany cognitive aging. The AHEI showed a nearly identical association with folic acid, at 0.068, and was additionally inversely associated with growth differentiation factor 15, or GDF15, a circulating protein that rises with mitochondrial stress, inflammation, and biological aging more broadly.

The rEDII analysis told a complementary story. Higher adherence to the reverse-transformed inflammatory index, meaning a diet with lower inflammatory potential, was inversely associated with leptin, insulin, GDF15, alkaline phosphatase, tumor necrosis factor receptor superfamily member 1B, and leukocyte counts. The coefficients ranged from -0.047 for TNFRSF1B, a receptor shed during tumor necrosis factor signaling, to -0.094 for leptin, the hormone produced by fat tissue that regulates appetite and energy balance. In practical terms, older adults whose diets carried a lower inflammatory burden showed lower levels of hormones and signaling molecules tied to adiposity, insulin action, inflammatory cascades, and cellular stress responses. Leukocytes, the circulating immune cells that often rise with systemic inflammation, were also lower, at a coefficient of -0.058.

What makes this pattern biologically coherent is that the affected markers cluster into recognizable physiological narratives. Folic acid, elevated in those following Mediterranean-style and healthy eating patterns, is a B vitamin central to one-carbon metabolism, DNA synthesis, and the regulation of homocysteine, an amino acid implicated in vascular and neurological damage. GDF15, reduced among those eating less inflammatory diets, has emerged in geroscience as one of the most compelling blood-based indicators of biological age, rising steadily with tissue stress and chronic disease. TNFRSF1B and leukocytes sit squarely within the inflammaging framework, the slow-burning, low-grade inflammation that accumulates with age and is implicated in frailty, cardiovascular disease, and dementia. Alkaline phosphatase, meanwhile, is an enzyme associated with liver and bone metabolism that has been linked to metabolic and vascular risk in prior research.

The associations held up under scrutiny. The authors report that the findings remained consistent across multiple sensitivity analyses, a robustness check designed to test whether the results were artifacts of particular modeling choices or subgroups. The biomarker quantification itself was supported by the Affinity Proteomics-Stockholm unit at SciLifeLab, reflecting the kind of high-throughput proteomic infrastructure that has transformed what population-based aging studies can measure. Where earlier cohorts might have tracked a handful of clinical chemistry values, this study could interrogate dozens of proteins and metabolites simultaneously, then map the survivors of statistical correction back onto known pathophysiological domains.

It is worth being precise about what the study does and does not show. The design is cross-sectional, meaning diet and biomarkers were measured at the same point in time, so the analysis cannot establish that eating well causes favorable biomarker levels. Reverse causation remains possible: people with higher biological burden may eat differently, and underlying illness can reshape both appetite and blood chemistry. The effect sizes, while statistically robust after correction, are modest, as is typical for dietary epidemiology in free-living populations. Yet the consistency of the domain-specific signals, the use of validated dietary indices, and the population-based sampling all strengthen the case that the observed signature reflects genuine biology rather than statistical noise. The study was approved by the Regional Ethical Review Board in Stockholm, and all participants or their next of kin provided written informed consent.

For the field of geroscience, the work lands at a moment of growing interest in identifying modifiable levers over the biology of aging. Diet is among the most tractable of these levers, and the new findings suggest that its influence is legible in the blood, distributed across metabolic hormones, inflammatory receptors, and even markers of glial activity in the brain. If future longitudinal and interventional studies confirm that shifting dietary patterns moves these biomarkers in the directions observed here, the humble food frequency questionnaire may become an even more powerful clinical tool, one that connects everyday eating choices to the molecular machinery of healthier aging.

Subject of Research: Associations between dietary patterns and blood-based biomarkers of aging in older adults

Article Title: Biological signature of dietary patterns in older adults: findings from a population-based study

Article References: DaCosta, R. A., Gregorio, C., Calderón-Larrañaga, A., Ornago, A. M., Mrhar, A., Ortolá, R., Fredolini, C., Vetrano, D. L., & Carballo-Casla, A. (2026). Biological signature of dietary patterns in older adults: findings from a population-based study. BMC Medicine, 24(1), Article 520. https://doi.org/10.1186/s12916-026-05202-2

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05202-2

Keywords: nutrition, biomarkers, aging, Mediterranean diet, inflammation, GDF15, GFAP, folic acid, geroscience, diet quality, older adults, population-based study

The star of the study is rhenium disulfide, or ReS2, a member of the transition metal dichalcogenide family that also includes the better-known molybdenum disulfide. What makes ReS2 special among two-dimensional materials is its unusually weak interlayer coupling: unlike MoS2, whose stacked layers interact strongly, the individual ReS2 sheets behave almost as if they were isolated, giving the material effectively two-dimensional electronic and optical properties even in thick crystals. For electrochemists, that decoupled structure is a gift. It means ions and electrons can access active sites throughout the material rather than only at the surfaces, and ReS2 has already earned a reputation as a high-rate pseudocapacitive energy storage material in earlier work. Pseudocapacitance, unlike the purely electrostatic charge storage of carbon double-layer capacitors, involves fast, reversible faradaic reactions at or near the electrode surface, allowing much higher charge storage per unit mass.

But ReS2 has two Achilles heels. First, like many layered sulfides, it suffers from structural deterioration during repeated cycling: as ions push in and out of the lattice, the material swells, cracks and eventually detaches from the current collector, killing the electrode. Second, its intrinsic electrical conductivity is poor, which throttles the very fast charge transport that pseudocapacitors need. The Lingnan Normal team set out to solve both problems at once with a single architectural move: anchoring ReS2 nanoparticles onto conductive, nitrogen-doped carbon nanosheets made by pyrolyzing folic acid. The carbon scaffold acts as a mechanical buffer that suppresses the aggregation of ReS2 particles and absorbs the mechanical strain of cycling, while the interconnected carbon network provides a highway for rapid electron transport and ion diffusion throughout the electrode.

The choice of folic acid as the carbon and nitrogen precursor is more than a laboratory curiosity. The vitamin molecule is rich in nitrogen atoms, carrying pteridine, amide and amine groups within a single compact structure, so when it is heated in the absence of oxygen it self-assembles into ultrathin carbon sheets with nitrogen already woven into the lattice. That built-in nitrogen doping matters electrochemically: nitrogen atoms in the carbon framework alter the local electronic structure, improve wettability with aqueous electrolytes and can contribute additional pseudocapacitance of their own. Previous studies have shown that folic acid pyrolysis yields nitrogen-doped graphitic carbon with well-defined structural evolution, and the approach has been used to host single-atom metal catalysts. Here, the researchers harnessed the same chemistry to create a conductive, nitrogen-rich mat on which ReS2 nanoparticles could be grown and anchored through a facile pyrolysis route.

The fabrication strategy follows a broader and rapidly growing trend in electrode engineering: hybridizing metal sulfides with biomass-derived or molecule-derived nitrogen-doped carbon. In recent years, teams have embedded tungsten disulfide in gelatin-derived honeycomb carbon networks, coupled tin sulfide with nitrogen-doped porous carbon, nanoconfined ReS2 in biomass-derived three-dimensional porous carbon architectures, and grown manganese sulfide on carbon sheets from coordination frameworks. The logic is always the same. The sulfide supplies high theoretical capacitance; the carbon supplies conductivity, structural confinement and extra surface area; and the nitrogen dopants boost both the electronic properties of the carbon and its chemical affinity for the sulfide phase. What distinguishes the new work is the molecular precision of the folic acid precursor, which delivers a high nitrogen content without the need for separate nitrogen sources or harsh post-treatments.

The electrochemical results are striking. The ReS2/nitrogen-doped carbon electrode delivered a specific capacitance of 758.78 farads per gram at 1 ampere per gram, a figure that places it among the better-performing transition metal dichalcogenide-carbon hybrids reported for pseudocapacitors. Equally important was the material’s superior rate capability, meaning it retained a large fraction of its capacitance as the charging current was increased. Rate capability is where many high-capacitance materials fail, because sluggish ion diffusion and poor conductivity cannot keep up with fast charge injection. The interconnected carbon network in the composite appears to have solved that bottleneck, allowing electrons to reach the ReS2 particles and ions to reach the active sites even at high current densities.

To test the material under realistic device conditions, the researchers constructed an asymmetric supercapacitor, pairing the ReS2/carbon composite as one electrode with a counter-electrode of complementary potential range. Asymmetric designs are the standard route to high-voltage aqueous supercapacitors: by using two electrodes with different operating windows, the total cell voltage, and with it the energy density, can be pushed well beyond what either electrode could achieve alone, since stored energy scales with the square of voltage. The resulting device achieved an energy density of 15.32 watt-hours per kilogram alongside a power density of 3.16 kilowatts per kilogram. For context, that energy density approaches the lower range of lead-acid batteries while retaining the rapid charge-discharge behavior and power delivery characteristic of supercapacitors, a combination that makes such devices attractive for regenerative braking, grid frequency regulation and portable electronics.

The work also speaks to a wider question in materials chemistry: how to design electrodes that survive the mechanical punishment of cycling. The nanosheet architecture of the composite is central here. Because the ReS2 nanoparticles are well anchored and spatially separated on the carbon sheets, they cannot coalesce into larger particles during cycling, and the flexible carbon matrix absorbs the volume changes that would otherwise fracture a bulk electrode. This confinement-and-buffering principle has proven its worth across the sulfide-carbon literature, from lithium and sodium battery anodes to supercapacitor electrodes, and the new study extends it to one of the least conventional dichalcogenides. The authors note that the composite demonstrates clear potential as an electrode for energy conversion and storage devices, positioning ReS2 hybrids alongside more established candidates.

Challenges remain before vitamin-derived rhenium electrodes power anything in your pocket. Rhenium is one of the rarest and most expensive elements on Earth, which likely confines ReS2 devices to niche, high-value applications unless loading can be minimized or the material recycled. The study reported here is an early-stage laboratory demonstration, and long-term cycling data, manufacturing scalability and full cost analysis will determine whether the architecture can make the leap from beaker to product. Still, the research adds an elegant entry to the catalog of molecule-derived carbon scaffolds, showing that a humble vitamin can be transformed into the conductive backbone of a high-performance energy storage material. As the demand for fast-charging, long-lived energy storage continues to grow, hybrid electrodes that marry reactive sulfides with nitrogen-doped carbon, whether derived from vitamins, biomass or metal-organic frameworks, are likely to remain at the forefront of the field, and this folic acid route offers a particularly clean and versatile way to build them.

Subject of Research: ReS2/nitrogen-doped carbon nanocomposites for pseudocapacitive supercapacitor electrodes

Article Title: ReS2 hybridized with folic acid-derived N-incorporated carbon sheets to enhance pseudocapacitive property

Article References: Wang, J., Yuan, Y., Liang, Q., Wang, X., Ma, L., Jiang, R., Cai, H., & Xi, Y. (2026). ReS2 hybridized with folic acid-derived N-incorporated carbon sheets to enhance pseudocapacitive property. Ionics. https://doi.org/10.1007/s11581-026-07560-6

Image Credits: AI Generated

DOI: 10.1007/s11581-026-07560-6

Keywords: supercapacitors, rhenium disulfide, nitrogen-doped carbon, folic acid, pseudocapacitance, nanocomposites, transition metal dichalcogenides, energy storage, pyrolysis, asymmetric supercapacitor, electrode materials, biomass-derived carbon

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