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Psychedelic and psychedelic-adjacent substances, including 3,4-methylenedioxymethamphetamine (MDMA) and classic serotonergic hallucinogens, are undergoing renewed therapeutic investigation and remain in non-medical use. Inadvertent exposure during early, unrecognized pregnancy is clinically plausible, yet pregnancy-specific safety evidence is limited. To map and synthesize the extent, characteristics, and limitations of primary human evidence on prenatal exposure to MDMA, psilocybin, and classic hallucinogens (lysergic acid diethylamide (LSD), mescaline/peyote, and N,N-dimethyltryptamine (DMT)/ayahuasca), and to identify clinically relevant evidence gaps for perinatal counseling and pharmacovigilance. Peer-reviewed primary human studies (cohort, case-control, cross-sectional, case series, case reports, and brief reports) describing prenatal exposure with reported maternal, obstetric, neonatal, congenital anomaly, or child neurodevelopmental outcomes were included. Animal and preconception-only studies were excluded. MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Library were searched from inception to March 2025. Supplementary methods included Google Scholar screening and citation tracking. Data were charted in duplicate using a standardized form and synthesized descriptively by substance and outcome domain. Consistent with scoping methodology, no formal risk-of-bias assessment or meta-analysis was undertaken. Twenty-three primary human sources (1968-2020) met inclusion criteria: MDMA (n = 11), LSD (n = 11), and mescaline/peyote (n = 1). No eligible primary human pregnancy outcome studies were identified for psilocybin or DMT/ayahuasca. The evidence base was heterogeneous and predominantly comprised small cohorts, teratology service follow-up reports, and case-based publications, frequently limited by self-reported exposure, polysubstance confounding, and inconsistent outcome definitions. Human evidence on prenatal psychedelic exposure remains sparse and methodologically constrained. Absence of data for several substances should not be interpreted as evidence of safety. Clinicians should counsel with explicit acknowledgment of uncertainty while supporting harm reduction and appropriate follow-up. Structured perinatal pharmacovigilance and ethically designed evidence-generation strategies are needed as therapeutic psychedelic research expands. What we know about psychedelic drug exposure during pregnancy Some people may be exposed to psychedelic drugs such as MDMA (“ecstasy”), LSD, or psilocybin during pregnancy, often before they realize they are pregnant. As interest in psychedelic therapies grows, clinicians are increasingly asked about possible risks to pregnancy and child development. In this review, we examined all available human studies that reported pregnancy or child outcomes following exposure to psychedelic or psychedelic-related substances. We found that the human evidence base is very limited and mostly consists of small observational studies, case reports, and follow-up data from teratology information services. Most available studies focus on MDMA or LSD, while there is little to no direct human pregnancy outcome data for substances such as psilocybin or ayahuasca. Because the available evidence is sparse and highly variable, it is not possible to reliably estimate the risks of miscarriage, birth defects, or long-term child development following psychedelic exposure during pregnancy. This review highlights important gaps in current knowledge and explains why careful, individualized clinical counselling is needed when such exposures occur. The findings are relevant for clinicians, patients, and researchers involved in drug safety and pregnancy care.

Although regulatory responses to safety signals have been studied, pregnancy-specific data and their dissemination to medical professionals remain unclear. This study examined the characteristics and temporal trends of teratological safety signals prompting the European Medicines Agency to implement risk minimization measures. A secondary aim was to investigate how information on these signals, independent of regulatory communication, was disseminated to medical professionals in the Netherlands. Teratological safety signals from 2002 to 2022 were retrieved from the European Pharmacovigilance Issues Tracking Tool. For each signal, we recorded the dates of market authorization, first spontaneous report, scientific publication, regulatory decision and dissemination through the Teratology Information Service (TIS) and Dutch professional journals. The source of the signal (spontaneous reports, scientific literature or otherwise) was assessed. Time intervals between events were calculated and visualized. Twenty-four safety signals pertaining to fetal teratogenesis were identified. At the time of regulatory action, medicines had been on the market for a median of 23.9 years (range 3.2-59.3). Cases or studies published in the scientific literature were the origin for most (n = 18, 75%) teratological safety signals. Amendments of the product information was a regulatory action for all signals; eight (33%) also triggered Direct Healthcare Professional Communications. Apart from these regulatory communications, information may have reached healthcare professionals through scientific literature or other channels, sometimes before and sometimes alongside regulatory decisions. Teratological safety signals are predominantly scientific literature-driven and often arise decades after marketing. Scientific publications and TIS may provide early guidance, frequently preceding regulatory decisions.

Etanercept is a tumor necrosis factor inhibitor frequently used to control ankylosing spondylitis (AS) in women of reproductive age, yet data on its safety during breastfeeding are limited. We report a case of an infant who developed somnolence, hypotonia, feeding difficulties, and a concomitant infection temporally associated with maternal etanercept therapy during lactation and discuss implications for breastfeeding. A 33-year-old woman with AS delivered a healthy female infant by cesarean section at 36 + 5 weeks' gestation and began exclusive breastfeeding. At 11 weeks postpartum, she initiated etanercept 25 mg subcutaneously once weekly for her active disease. During treatment, the infant developed prolonged sleep, somnolence, feeding difficulty, and hypotonia, followed within a week by low-grade fever, cough, and nasal congestion. After three doses, etanercept was discontinued, and she was referred to our teratology information service. Approximately 2 weeks after the last dose, the infant's respiratory symptoms worsened, and diarrhea developed, prompting emergency admission. Laboratory evaluation showed leukocytosis, elevated C-reactive protein, and a nasopharyngeal swab, which was positive for rhinovirus/enterovirus. Symptoms resolved with supportive care and azithromycin by treatment days 4-5. At 9 months of age, the infant has had no other health issues. This case illustrates the difficulty of interpreting adverse events in breastfed infants exposed to maternal biologic medications. Although current evidence suggests no clinically severe adverse effects, minimal infant exposure, and a low risk of clinically relevant immunosuppression with etanercept during breastfeeding, individualized counseling and careful monitoring of exposed infants remain essential.

The evidence gap relating to the risk of congenital anomalies (CA) associated with first trimester medication exposure in pregnancy is well recognized. We describe the EUROmediCAT network and databases, and the methodological approach to pregnancy pharmacovigilance. Multidisciplinary expertise includes CA diagnosis and epidemiology, pharmacoepidemiology, pharmacology and teratology. The EUROmediCAT central database comprises standardized data from 19 EUROCAT CA registries in 14 countries, including more than 40 000 CA cases 1995-2021 with first trimester medication exposure data recorded, and a population coverage of 14.6 million births, growing by more than 650 000 births per year. The distributed database enables federated data analysis across eight countries which can link data from CA registries to electronic healthcare data, with population coverage of up to 900 000 births per year for linkage to maternal prescriptions, of which 300 000 births per year for linkage also to data on all births. The databases have enabled a variety of study designs: case-malformed control studies, cohort studies, disease cohort studies, signal detection studies, prevalence and ecological studies, and medication utilization studies. A key strength is that studies of CA risk can address accurately the specificity of risk by type of CA. EUROmediCAT presents a unique data and expert resource for tackling the enormous evidence gap regarding the safety of medication during pregnancy. There is a well‐recognized need for more evidence about the safety of medication use in early pregnancy to guide optimal medication choice. This paper describes the EUROmediCAT network and its databases, and how these databases can be used to generate evidence about medication safety in pregnancy. A single central database includes data from congenital anomaly registries in 14 countries of Europe, with information on medication exposure of each case. This covers a population of 14.6 million births 1995–2021, and is growing by more than 650 000 births per year. Databases accessible in eight countries link congenital anomaly registries to prescription data (covering over 900 000 births per year), and to all births (covering over 300 000 births per year). These data can also be shared for large scale research. A key strength of the EUROmediCAT network and databases is that particular attention is paid to accurate information on the risk of specific types of congenital anomaly. EUROmediCAT presents a unique data and expert resource for tackling the enormous evidence gap regarding the safety of medication during pregnancy.

Since 2008, the open-access internet portal "Embryotox" has provided evidence-based information on drug safety during pregnancy and breastfeeding. The German website, designed for health care professionals, comprises fact sheets about 400 drugs and is maintained by the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy at the Charité - Universitätsmedizin Berlin. In 2024, it was accessed more than 5 million times. This study aimed to evaluate who is using the website, how it is being used, and to what extent it meets users' needs. Data were collected between 2022 and 2023 through a sequential mixed methods design incorporating explanatory and exploratory elements. Online questionnaire 1 contained questions on user characteristics, clinical specifics of use, comprehensibility, and changes in risk assessment or drug therapy following fact sheet use. Qualitative data were generated through semistructured phone interviews, with interviewees sampled from the main user groups identified in questionnaire 1 (patients, physicians, pharmacists, and midwives). Kuckartz's content analysis was used to analyze data on users' trust and the functions of website use for different stakeholder groups. Online questionnaire 2 collected data from the main user groups on their decision-making based on Embryotox fact sheets. This questionnaire was developed based on the findings from semistructured interviews on the functions of website use. Answers in both questionnaires included multiple-choice options or ratings on a Likert scale from 0 (not at all) to 10 (fully); data were analyzed using descriptive statistics. Questionnaire 1 was completed by 14,562 users, including 10,860 patients, 1676 physicians, 550 pharmacists, and 364 midwives. Of the physicians, 27.2% (456/1676) were obstetricians and gynecologists, and 22.7% (381/1676) were general practitioners. For physicians, the mean of comprehensibility ratings was 9.39 (pharmacists 9.25; midwives 9.14), and for patients 8.80. Following fact sheet use, 66.6% (9694/14,562) of all users changed their risk perception, and 22.3% (2252/10,083) of users in a specific treatment setting considered changing drug treatment. Qualitative content analysis revealed that users highly trusted the information in the fact sheets for a number of reasons, including recommendations from other users, the scientific basis of the website, and the authority of the Embryotox Center as a university-based specialist department for drug safety in pregnancy and lactation. Functions of fact sheet use differed depending on the stakeholder group. A total of 793 users, mostly physicians and patients, fully completed questionnaire 2, specifying typical clinical situations and benefits of fact sheet use for shared decision-making. Benefits included facilitating the decision-making process and increasing confidence in it. The information provided in the Embryotox fact sheets was generally perceived as both comprehensible and trustworthy, supporting and facilitating the decision-making process. Embryotox is used successfully by health care providers and patients in routine health care settings, helping to improve drug safety for pregnant and breastfeeding women.

The cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) serves as a central immunotransmitter that propagates stimulator of interferon gene-dependent (STING-dependent) innate immunity across tissues; however, how microenvironmental metabolites regulate its spatiotemporal dynamics remains unknown. Here, we identified polyamines (spermine and spermidine) as critical rheostats controlling 2'3'-cGAMP functionality. Mechanistically, polyamines sequestered 2'3'-cGAMP into polymer-like aggregates, blocking intercellular propagation and suppressing intracellular STING activation by reducing ligand-receptor binding affinity. Deficiency of spermidine and spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, elevated polyamine levels to entrap extracellular 2'3'-cGAMP and inhibit STING activation. Synergistic administration of endogenous 2'3'-cGAMP with SAT1 stabilizer N1,N11-diethylnorspermine restored 2'3'-cGAMP bioavailability and STING signaling, facilitated type I interferon responses to reprogram immunologically suppressive tumors into immunologically active states and enhanced tumor clearance. Our study established polyamine-cGAMP interactions as a critical spatiotemporal regulatory mechanism for tissue-level immunity, providing a unified model for metabolite-mediated cyclic GMP-AMP synthase-STING (cGAS-STING) regulation across diseases.

Programmed death-ligand 1 (PD-L1) plays a crucial role in tumor immune evasion, making it an important biomarker and a validated target for cancer immunotherapy. In this study, we designed, synthesized, and preclinically evaluated a series of novel PD-L1-targeted radiotracers based on a phenoxymethyl-biphenyl scaffold. Our design strategy was to incorporate different functional amino acid residues and flexible linkers between the phenoxymethyl-biphenyl scaffold and the DOTA chelator. Among the six radiotracers, [68Ga]Ga-PEG-PRO-ZB exhibited high stability, strong binding affinity to PD-L1 (KD = 19.3 ± 0.6 nM), and low nonspecific uptake. Micro-PET/CT imaging confirmed its ability to detect PD-L1 expression in multiple tumor models. Notably, [68Ga]Ga-PEG-PRO-ZB also enabled the dynamic monitoring of PD-L1 expression following immunotherapy. These results demonstrate that [68Ga]Ga-PEG-PRO-ZB can effectively visualize PD-L1 expression in vivo, offering valuable insights into the rational design and optimization of small-molecule based PD-L1 radiotracers.

The stimulator of interferon genes (STING) is a critical mediator of innate immunity against cytosolic DNA pathogens, requiring precise regulation to balance antiviral defense and immune tolerance. While lipid metabolism influences immune signaling, the role of stearoyl-CoA desaturase 1 (SCD1), a key enzyme converting saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), in STING activation remains unexplored. Here, we identify SCD1 as a metabolic checkpoint that licenses STING activation through biophysical membrane remodeling. Mechanistically, SCD1-generated MUFAs incorporate into endoplasmic reticulum (ER) phospholipids, enhancing membrane curvature and fluidity. This biophysical remodeling facilitates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) binding to STING and promotes its dimerization, enabling downstream TBK1-IRF3 signaling and type I interferons (IFNs) production. Consequently, Scd1 deficiency or pharmacological inhibition impairs STING activation, attenuates antiviral responses against herpes simplex virus-1 (HSV-1), and exacerbates viral replication in vitro and in vivo. Conversely, MUFAs supplementation rescues STING activation in Scd1-deficient models. Our findings establish SCD1-mediated lipid desaturation as a fundamental regulator of STING-driven immunity, highlighting its therapeutic potential for disorders of aberrant STING activation.

This exploratory pilot study evaluated whether subchronic late-gestational oral nicotine exposure alters postpartum maternal behavior in Wistar rats. Twelve pregnant Wistar rats were obtained in three successive intake batches and randomly assigned to experimental or control groups. Control animals received a 2% saccharin solution; experimental animals received nicotine (nominal 200 μg/mL) in 2% saccharin solution ad libitum from gestational day 7 through parturition. The initial concentration of 200 μg/mL produced two maternal deaths and one embryonic reabsorption in the first experimental batch; the solution was diluted approximately 1:3 to ∼50 μg/mL for the third experimental batch. Postpartum maternal behavior was scored from 15-min light-phase video samples (three 5-min blocks at 5-s instantaneous sampling) on each of the 14 postpartum days. Dependent variables were daily frequency counts of 19 ethogram behaviors organized into proximal, nest-related, motor, and self-maintenance categories. Primary analyses were 2 × 14 mixed repeated-measures ANOVAs. Fluid consumption, litter parameters, and cohort attrition are also reported. Experimental dams reduced solution consumption by approximately 81% relative to their pre-nicotine water baseline, indicating that actual nicotine exposure was substantially below the nominal concentration. Among the three surviving dams per group, proximal maternal behaviors showed no reliable group differences on either parametric or non-parametric tests. The clearest between-group difference was in eating frequency (controls > experimentals; F(1, 4) = 48.96, p = .002, ηp2 = 0.92). A significant Day × Group interaction was observed for locomotion, concentrated on postpartum days 11-12. In this small pilot, subchronic late-gestational nicotine exposure did not produce consistent alterations in core proximal maternal behaviors among surviving dams, but was associated with substantial gestational losses, reduced maternal fluid intake, a qualitative low-pup-birth-weight observation, and a postpartum eating-frequency difference that cannot be unambiguously attributed to nicotine pharmacology. The findings are hypothesis-generating and motivate adequately powered replication with cotinine verification and gravimetric pup-weight measurement.

Rapid global warming imposes profound stress on terrestrial ecosystems, both past and present, making it essential to understand how ecosystems respond to climate change in deep time. The Toarcian hyperthermal event (~183 Ma) provides a natural case study for investigating these dynamics. Using the Schandelah-1 core from the North German Basin, we conducted teratological analyses of terrestrial vegetation, revealing pronounced morphological variation. Despite transport and preservation biases, the persistence and diversity of malformations indicate widespread reproductive disruption alongside adaptive strategies, including physiological plasticity and microclimatic buffering, probably driven by thermal stress. Multivariate analyses further confirm significant shifts in pollen malformation during peak warming, showing that terrestrial vegetation was simultaneously highly sensitive and resilient. These results provide critical insights into how land plants coped with rapid thermal stress during this interval, offering a deep-time framework for understanding ecosystem responses to past environmental change.

Valproic acid (VPA) is a well - known teratogen and neuro-teratogen affecting many animals including humans. In rodents, prenatal VPA may induce a wide range of malformations and/or neurodevelopmental disorders depending on the time of administration and dose. We previously found that early postnatal administration of VPA in mice induced autistic like behaviour, and in the brain changes in gene expression and increased oxidative stress. S-adenosylmethionine (SAMe) normalized these deviations. We now assessed the possible alleviation by SAMe of the injuries caused by VPA administration during days 8.5, 9.5 of gestation on brain oxidative and nitrosative stress. ICR mice received intraperitoneally 300 mg/Kg VPA with or without 30 mg/kg SAMe, or a mixture of VPA and SAMe in the same ration. Fetuses were studied on Embryonic day 15.5. VPA induced fetal growth retardation, 32.5% of exencephaly, high resorption rate and, in the brain, increased Malondialdehyde (MDA) concentrations, increased antioxidant enzyme activity and elevated expression of antioxidant genes with increased expression of NOS1 and NOS2 genes, implying increased nitrosative stress. SAMe alone did not cause changes in the parameters tested. The addition of SAMe to VPA, abolished the VPA-induced damage. Administration of the mixture of VPA and SAMe did not induce any embryonic damage or changes in the redox potential of the brain, except for an unexplained up regulation of SOD1 and SOD2 genes. It is concluded that SAMe, an epigenetic modulator, neutralizes VPA's neuro-teratogenic effects when administered together with VPA during neurulation, like its postnatal effects.

Prenatal alcohol exposure (PAE) can disrupt development, leading to alterations in physical, health, and behavioral outcomes, referred to as fetal alcohol spectrum disorders (FASD). Although alcohol likely impacts fetal development through many mechanisms, PAE could impact metabolism of choline, an essential nutrient that is important for brain development and function. Importantly, both preclinical and clinical studies show that choline supplementation can improve performance on hippocampal-dependent behavioral tasks, even when administered postnatally. However, the mechanisms by which choline mitigates prenatal alcohol-induced neurocognitive deficits are not well understood. Thus, the present study examined whether PAE leads to long-lasting changes in choline metabolism in the hippocampus and plasma of adolescent animals and if effects are modified by choline. From postnatal day (PD) 4-9, rat pups were given ethanol (EtOH; 5.25 g/kg/day) or sham intubations. From PD 10-30, subjects received s.c. choline chloride (100 mg/kg/day) or saline. Plasma and hippocampus were collected on PD 35 and choline metabolite levels were analyzed. Neither EtOH nor choline led to long-lasting changes in choline levels. However, EtOH-exposed females had reduced hippocampal betaine and plasma betaine:choline ratios. Plasma cystathionine was elevated in EtOH-exposed females treated with choline, suggesting choline activates anti-oxidative stress and anti-inflammation pathways among EtOH-exposed subjects. Choline alone increased homocysteine among females. In contrast, choline supplementation increased plasma SAM:SAH ratios in EtOH-exposed males, suggesting choline is modifying DNA methylation. Overall, these results provide insights to sex-specific mechanisms of action in which choline supplementation alters choline metabolic pathways in FASD.

Autosomal-dominant polycystic kidney disease (ADPKD) remains refractory to curative therapy partly due to the lack of human models that recapitulate its adult-onset nature, genetic context, and multi-segment origin. Here, we established expandable, multi-lineage adult renal organoids (MAROs) directly from surgical specimens of ADPKD patients and healthy donors, creating a three-dimensional (3D) high-content screening platform. Patient-derived MAROs faithfully reproduced hallmark cystogenic features, including elongated primary cilia, polarity disruption, and elevated Rho GTPase/planar cell polarity (PCP) signaling. Single-cell transcriptomics of PKD1/PKD2-mutant organoids revealed genotype-specific alterations. Genetic ablation of IFT88 disrupted cilia and selectively attenuated Rho/PCP activity in mutant backgrounds, supporting a cilia-dependent cyst-activating (CDCA) mechanism in cystogenesis. Microfluidic perfusion accelerated cyst expansion and amplified Rho/PCP signaling. A high-throughput drug screen identified Rho GTPase inhibitors, including ML141, as effective cyst-reducing agents across genotypes without compromising viability. Our findings establish a patient-derived organoid platform that captures ADPKD pathology and nominates Rho pathway modulation as a therapeutic strategy.

The nucleolus, a membrane-less organelle within the nucleus, plays a fundamental role in ribosome biogenesis with cellular functions across diverse physiological and pathological states. While its multilayered, liquid-like architecture is formed by complex interactions between nucleolar proteins and nucleic acids, the regulatory mechanism of nucleoplasmic components on nucleolus remains poorly understood, particularly heterochromatin and its associated proteins. In this study, we revealed that Polycomb repressive complex 2.1 (composed of PRC2 core subunits plus Polycomb-like (PCL) homolog), associating with H3K27me3-enriched heterochromatin, accumulates surrounding the nucleolus to form a ring-like structure. Notably, as a key PRC2.1 component, PCL2 undergoes phase separation, while the intrinsically disordered region (IDR) in PCL2 regulates both the fluidity of the condensates and its interaction with nucleolar protein nucleophosmin (NPM1). PCL2 is a key regulator to facilitate NPM1 pentamerization and interaction among nucleolar components, ensuring the efficient progression of rRNA and protein synthesis. Taken together, our findings reveal that PRC2.1(PCL2) plays a crucial role in maintaining nucleolar integrity and rRNA synthesis, highlighting that PRC2.1(PCL2) is required for cell proliferation.

β-Arrestins 1 and 2 are multifunctional adaptor proteins1 that regulate the signalling of G-protein-coupled receptors (GPCRs), the largest class of receptors, which impact nearly all aspects of physiology and are one of the most common drug targets2. Although β-arrestins interact with a wide array of signalling effectors at many GPCRs, it is unclear how β-arrestins promote such varied functions. Here we show that β-arrestins undergo liquid-liquid phase separation, forming condensates that regulate GPCR function. We show that condensation is specific to visual arrestins and β-arrestins, and demonstrate that β-arrestin oligomerization occurs in proximity to the GPCR to regulate GPCR functions such as internalization and signalling. Our work provides a paradigm for β-arrestin condensates as regulators of GPCR function, with liquid-liquid phase separation serving as an important promoter of signalling compartmentalization at GPCRs.

Breastfeeding women are often concerned about their milk supply. To increase their milk supply, a galactagogue may be used. Galactagogues are foods, herbals, or medicines that increase milk production or flow. There is limited information on the effectiveness of galactagogues. We aimed to evaluate the use and perceived effectiveness of prescribed and over-the-counter galactagogues in the Netherlands. We performed cross-sectional analyses among breastfeeding participants using a galactagogue in the cohort study the Dutch Pregnancy Drug Register. Their baseline characteristics were compared to the general breastfeeding cohort. Timing and duration of galactagogue use and the perceived effectiveness were explored. The perceived effectiveness of domperidone was compared with that of over-the-counter products. Of the 6623 breastfeeding participants, 381 (5.8%) used a galactagogue. Participants using a galactagogue were more likely to breastfeed for the first time and to have a twin pregnancy or a premature birth than the general breastfeeding cohort. A total of 29 different galactagogues were used. The most commonly used galactagogue was oxytocin (37.8%) followed by "Boezemvriendjes" (25.7%) and domperidone (24.9%). Overall, 69.2% of the participants reported that the galactagogue influenced their milk and 41.0% indicated it led to an increase in production. There was no significant difference in the percentage of participants experiencing an increase in milk production between domperidone and over-the-counter products. In this study, a variety of galactagogues were used including prescribed and over-the-counter products. Almost half of the participants experienced an increase in milk production, regardless of the galactagogue used.

Chemoresistance remains a major therapeutic challenge in gastric cancer (GC). We report that the long non-coding RNA (lncRNA) Linc00347 is markedly upregulated in oxaliplatin (Oxa)-resistant GC tissues relative to Oxa-sensitive counterparts, and its elevated expression correlates with poor patient prognosis. Functionally, Linc00347 conferred Oxa resistance and accelerated tumor growth in vivo by repressing ferroptosis. Mechanistically, Linc00347 directly interacted with the RNA-binding protein YBX1 and prevented its proteasomal degradation by recruiting the deubiquitinase USP10. The stabilized YBX1 then served as an m5C 'reader' to specifically recognize and bind FoxO6 mRNA m5C-modified by the methyltransferase NSUN2, thereby enhancing FoxO6 mRNA stability. Crucially, FoxO6 depletion restored ferroptosis sensitivity and overturned Linc00347-driven chemoresistance. Our results establish the Linc00347/YBX1/FoxO6 axis as a novel and therapeutically exploitable driver of ferroptosis suppression in GC chemoresistance.

Sodium valproate (VPA) is an established teratogen that is prescribed worldwide. Although congenital anomalies and neurodevelopmental impairments are well described in those affected by in utero VPA exposure, limited data are available regarding the physical health impacts. We aimed to document, via caregiver reporting, the physical health outcomes for a cohort of in utero VPA-exposed individuals compared with an unexposed group. This cross-sectional observational study collected primary data via questionnaire from primary caregivers of individuals exposed and unexposed to VPA in utero. Information collected related to maternal health, pregnancy, offspring health and neurodevelopment. Participants were recruited from the UK, Ireland, New Zealand, the United States, and Australia. Reported physical health was compared between those exposed to VPA monotherapy in utero (n&#x2009;=&#x2009;88) and an unexposed group (n&#x2009;=&#x2009;18). Physical health concerns were reported in a median of 6 of 12 organ systems for those with VPA exposure of 1000&#x2009;mg per day or greater, 5 systems with exposure less than 1000&#x2009;mg VPA per day, and 1 in the unexposed group. The VPA-exposed group reported poorer health (p&#x2009;<&#x2009;.001), increased difficulty (p&#x2009;<&#x2009;.001), pain or distress (p&#x2009;<&#x2009;.001), and increased limitation of daily activities (p&#x2009;<&#x2009;.001). Reported health complaints were wide ranging and extended beyond congenital anomalies. This study highlights increased reporting of physical health challenges in those exposed to VPA in utero, the multimorbidity impact of which affects quality of life and can persist into adulthood. Further study is warranted to ascertain accurate prevalence of these symptoms among individuals harmed by VPA in utero.