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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.

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.

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.

Inflammasome activation and pyroptosis are central to innate immune responses and play either protective or detrimental roles in host defense. Inhibiting these processes holds significant therapeutic promise for diseases exacerbated by inflammasome activation. However, clinically targeting this pathway remains challenging, as blocking pyroptosis may trigger alternative cell death pathways. In this mini-review, we summarize bacterial and viral infections in which inflammasome activation and pyroptosis are detrimental to host defense, explore the mechanisms underlying cell death switching, and discuss how effectively blocking multiple cell death pathways and potential interconversions represents a key consideration for current intervention strategies.

Pain management during pregnancy poses a considerable challenge in everyday clinical practice. The relief of maternal discomfort must be weighed against the potential risks of using medication (nonsteroidal anti-inflammatory drugs, paracetamol, steroids, opioids, gabapentinoids). The current data on congenital anomalies, complications during pregnancy, neonatal adaptation or withdrawal symptoms, and long-term psychomotor developmental disorders in children exposed in utero must be taken into account. However, refraining from treating chronic maternal pain during pregnancy can also cause problems for the child's development. Given the limited research findings, prescribing physicians must clarify the advantages and disadvantages of treatment strategies through informed, joint decision-making with their patients. This overview is intended to serve as an evidence-based guide for optimizing pain management during pregnancy while minimizing risks to offspring. Die Schmerztherapie während der Schwangerschaft stellt eine erhebliche Herausforderung im klinischen Alltag dar. Die Linderung der Beschwerden der Mutter muss gegen die potenziellen Risiken einer Anwendung von Medikamenten (nichtsteroidale Antiphlogistika, Paracetamol, Steroide, Opioide, Gabapentinoide) abgewogen werden. Dabei ist die aktuelle Datenlage zu angeborenen Anomalien, Komplikationen im Schwangerschaftsverlauf und neonatalen Anpassungs- bzw. Entzugssymptomen, aber auch zu langfristigen psychomotorischen Entwicklungsstörungen der intrauterin exponierten Kinder zu berücksichtigen. Auch der Verzicht auf eine Therapie chronischer Schmerzen in der Schwangerschaft kann Probleme für die Entwicklung des Kindes mit sich bringen. Angesichts der begrenzten Forschungsergebnisse müssen die verordnenden ÄrztInnen die Vor- und Nachteile von Behandlungsstrategien durch eine informierte gemeinsame Entscheidungsfindung mit den Patientinnen klären. Diese Übersicht soll als evidenzbasierter Leitfaden der Optimierung der Schmerzbehandlung während der Schwangerschaft bei gleichzeitiger Minimierung der Risiken für die Nachkommen dienen.

Clinical lactation studies are valuable to guide pharmacotherapy during breastfeeding, but are not easy to conduct. This paper reports on challenges and mitigation strategies while conducting the UmbrelLACT study, a prospective observational lactation study. The UmbrelLACT study includes breastfeeding women taking a relevant medicine (eg, absence of safety evidence during lactation) and after feasibility verification (eg, access to bioanalytical assay). Participants collect human milk samples at home over 24 hours. Optionally, maternal and infant blood samples are collected, together with self-reported questionnaires on clinical maternal and child variables. Medicine concentrations and estimated infant exposure (eg, daily and relative infant dose) are determined. Regarding informed consent, study objectives should be carefully phrased to prevent pharmacotherapy avoidance due to a lack of safety information. On sample collection, the study team should provide all necessary materials if not available at home, including an electric breast pump. Due to the milk expressions over 24 hours, the infant might miss soothing moments. This can be mitigated by giving the breast after expressing the milk for study purposes, creating alternative soothing moments. Sample handling might be complicated by additional steps needed for certain compounds. A bioanalysis method should be available or developed for the milk matrix. Finding the assay might be challenging, but it can be facilitated by a network of specialised labs. In the UmbrelLACT study, pharmacokinetic values are collected fragmentarily. This results in the need for data pooling with data from the literature. In contrast, at-home sampling and multidisciplinary collaboration are clear strengths. It is feasible to tailor the approach to each participant and compound, to minimise the burden on the patient and their family. While there are limitations related to the pragmatic design, the opportunities of this lactation study outweigh the challenges to result in clinically significant scientific observations. NCT06042803.

Cochlear hair cells are the mechanosensitive receptor cells responsible for detecting sound information. They are characterized by their apical F-actin-filled stereocilia that are essential for mechano-electrical transduction. Previously, we and other groups reported that RNA Binding Motif Protein 24 (RBM24) plays pivotal roles in stereocilia development and maintenance by regulating pre-mRNA alternative splicing and mRNA stability. In the present work, we show that exon 4 of the mouse Rbm24 gene is subjected to alternative splicing. Inclusion of exon 4 in Rbm24 mRNA results in premature translational stop, giving rise to a short isoform of RBM24 (RBM24-S). Notably, while sharing the same RNA-recognition motif, the canonical RBM24 long isoform (RBM24-L) and RBM24-S can bind different mRNA targets to affect their splicing and/or stability. Deletion of Rbm24 exon 4 in mice abolishes the expression of Rbm24(+e4) transcripts that encode for RBM24-S, and both homozygote and heterozygote mice suffer from severe hearing loss. Further investigations revealed that Rbm24 exon 4 deletion leads to stereocilia disorganization and eventually hair cell loss. Moreover, overexpression of RBM24-L in the hair cells leads to significant stereocilia deficits as well as profound hearing loss. Finally, we identified several RBM24 targets such as Strc, whose dysregulation contributes to stereocilia disorganization as well as hearing loss in Rbm24 deficient mice. Taken together, our present data suggest that Rbm24 is subjected to alternative splicing and appropriate RBM24 expression levels are important for stereocilia integrity and hearing function.

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 objective of this systematic review and meta-analysis was to assess the risk of any and major congenital malformations and other adverse pregnancy outcomes following maternal exposure to glucagon-like peptide-1 receptor agonists during the periconceptional period and pregnancy. We conducted a systematic literature search of the PubMed, MEDLINE, Embase, Web of Science, and Reprotox electronic databases from inception through January 2026. Seven cohort studies encompassing over 40,000 exposed pregnancies were included. Maternal exposure to glucagon-like peptide-1 receptor agonists at any time during pregnancy was not associated with a statistically significant increase in any congenital malformations (OR, 1.11; 95% CI 0.82-1.51). First-trimester exposure did not significantly increase the risk of major congenital malformations (OR, 1.39; 95% CI 0.73-2.65). Furthermore, no significant risk increase was observed for stillbirth, spontaneous abortion, small for gestational age, or preterm birth. A significant association for urinary malformations was noted (OR, 1.24; 95% CI 1.05-1.47) based exclusively on unadjusted data. Maternal exposure to glucagon-like peptide-1 receptor agonists does not demonstrate a statistically significant association with major congenital malformations, stillbirth, spontaneous abortion, small for gestational age, or preterm birth. The urinary malformation signal relies on unadjusted estimates, likely reflecting residual confounding. These findings provide cautiously reassuring evidence regarding reproductive safety, though the certainty of evidence remains low.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC) and confers resistance to immunotherapy. However, the underlying mechanisms remain unclear. We aimed to elucidate how the lipid-rich microenvironment of MASLD-HCC drives immune suppression and to identify actionable targets. Dendritic cell (DC)-CD8+ T cell interactions in HCC tissues were analyzed by multiplexed immunofluorescence staining. Mechanistic studies employed high-fat diet (HFD)-induced MASLD-HCC mouse models, genetic or pharmacological inhibition of Tim-3, and DC depletion or adoptive transfer. Lipid peroxidation, ferroptosis, and immune interactions were assessed using flow cytometry, transcriptomics, and functional assays. The therapeutic efficacy of Tim-3 blockade, alone or combined with anti-PD-1 therapy or lenvatinib, was evaluated in preclinical models. HFD reshaped the hepatic tumor immune microenvironment by inducing DC depletion and CD8+ T cell dysfunction, facilitating liver tumor progression. In human steatohepatitis-related HCC, DC infiltration and DC-CD8+ T cell interactions were markedly impaired, and high DC-specific Tim-3 expression correlated with poor prognosis. Mechanistically, the lipid-rich microenvironment induced DC depletion via Tim-3-dependent lipid peroxidation and ferroptosis. Genetic or pharmacological inhibition of Tim-3 in DCs attenuated lipid peroxidation, restored DC survival and CD8+ T cell activation, and suppressed tumor growth. Moreover, Tim-3 blockade synergized effectively with both anti-PD-1 and lenvatinib to achieve sustained tumor control. Our findings establish Tim-3 as a pivotal regulator of DC ferroptosis in metabolic liver cancer. Combining Tim-3 blockade with standard therapies represents a promising strategy to restore immune surveillance in MASLD-HCC. Our findings identify Tim-3 as a crucial metabolic immune checkpoint that governs dendritic cell ferroptosis and dendritic cell-mediated antitumor immunity in metabolic liver cancer. Targeted blockade of Tim-3 in dendritic cells holds great therapeutic potential for the treatment of steatohepatitis-related hepatocellular carcinoma, particularly for patients with metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma who exhibit resistance to anti-PD-1 therapy.

Alpha-terpineol (α-terpineol), a ubiquitous monoterpenoid alcohol found in numerous essential oils, is widely employed in cosmetics, perfumes, and aromatic therapies. Despite its extensive application, concerns regarding its potential reproductive and developmental toxicity remain inadequately characterized, particularly concerning specific teratogenic effects and underlying molecular mechanisms. This study presents novel findings, demonstrating that α-terpineol exposure during the critical organogenesis period significantly induces developmental toxicity in Wistar rat fetuses. α-terpineol was administered at the doses of 0, 75, 150, and 300 mg/kg with a dose volume of 5 mL/kg. We report dose-dependent embryotoxic and teratogenic effects, including reduced fetal weight and a spectrum of severe skeletal malformations such as anophthalmia, club foot, micrognathia, phocomelia, and irregularities in the vertebral column, ribs, and limb bones. Crucially, our comprehensive gene expression analysis revealed statistically significant alterations in the expression patterns of HOXD13 and GDF11, two pivotal genes essential for skeletal patterning and limb development. The observed downregulation of these genes suggests a potential molecular association into α-terpineol-induced teratogenesis. These findings underscore the significant developmental risks associated with α-terpineol exposure during pregnancy and provides insights into potential molecular changes underlying its teratogenic potential, warranting further investigation into human health implications and the establishment of safe exposure limits for this widely used compound.

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.

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.

Fetiform teratoma (FT) and fetus-in-fetu (FIF) represent a spectrum of rare retroperitoneal masses containing organoid structures. While FIF is classically defined by the presence of a vertebral axis, FT lacks this organized skeletal development. Distinguishing between these entities is critical given the malignant potential associated with FT, estimated at approximately 10%. We report a case of a 5-month-old male presenting with a large (12&#x2009;cm) retroperitoneal mass and elevated alpha-fetoprotein (AFP 56.8&#x2009;IU/mL; age-matched reference <7&#x2009;IU/mL). Macroscopically, the resected tumor featured a distinct rudimentary digitiform projection with a nail bed. Histopathology demonstrated extensive organoid differentiation, including gastrointestinal loops with muscular layers, respiratory epithelium, and well-formed pancreatic parenchyma and adrenal cortex. Despite the complex organogenesis and limb-like morphology, the absence of a vertebral column or ossified long bones supported a diagnosis of mature cystic teratoma with fetiform features (FT) over FIF. This report highlights the diagnostic ambiguity within the "gray zone" of these lesions and emphasizes the role of axial skeletal organization and serum AFP levels as complementary tools for classification and oncologic surveillance.

Meiotic progression is critically dependent on precise regulatory networks to ensure genomic stability. SMEK1 is recognized as a regulatory subunit of the protein phosphatase 4 complex. However, its potential phosphatase-independent functions in mammalian meiosis remain largely unexplored. Given the association of genetic variants near the SMEK1 locus with human infertility, we sought to define its specific role and mechanism in murine spermatogenesis. We generated a germ cell-specific Smek1 knockout mice model by crossing Smek1f/f mice with Stra8GFP-Cre mice. The phenotypic consequences were mainly assessed by histological analysis, chromosome spreading, and immunofluorescence staining. The molecular mechanisms were predominantly investigated using chromatin-immunoprecipitation, luciferase reporter assays, and co-immunoprecipitation analysis both in&#xa0;vivo and in&#xa0;vitro studies. Germ cell-specific ablation of Smek1 resulted in complete sterility due to a total arrest of spermatogenesis. The deficiency of Smek1 caused severe defects in prophase I, including an increased proportion of diplotene-stage spermatocytes, impaired synaptonemal complex dynamics, incomplete DSB repair, and a reduction in crossover. Notably, a subset of spermatocytes survived the initial checkpoint monitoring but arrested at metaphase I with a disrupted spindle structure and hyperactivation of the spindle assembly checkpoint. Mechanistically, we identified that SMEK1 functions independently of PP4 as a transcriptional repressor. It binds to the promoter of the deubiquitinating enzyme gene USP10. In the absence of SMEK1, increased USP10 protein stabilized BUBR1 (the core spindle assembly checkpoint component) and therefore delayed further progression beyond the metaphase I stage. Our study discovered a novel role for SMEK1 as a transcriptional regulator essential for meiotic progression. This SMEK1-USP10-BUBR1 pathway provides a fundamental mechanistic insight into the causes of male infertility and identifies a potential therapeutic target for human azoospermia and infertility.

Ribosome biogenesis, a process of producing ribosomes, plays an essential role in cell survival, proliferation and apoptosis. Nucleostemin (NS) is a conserved nucleolar protein highly expressed in proliferating cells but markedly reduced in differentiated cells. Previous studies on mammalian systems have shown that loss of NS triggers p53-dependent apoptosis and impairs ribosomal RNA (rRNA) processing. In this study, using the Drosophila wing imaginal disc, which is a proliferating epithelial tissue, we demonstrate that depletion of Ns1, the Drosophila homolog of mammalian NS, induces extensive p53-independent apoptosis and suppresses global translation. Notably, we find that Ns1 is required not only for rRNA processing but also for maintaining global ribosomal protein (RP) abundance. Loss of Ns1 leads to a reduction in 65 RPs. Furthermore, we show that Ns1 deficiency upregulates the Xrp1/Irbp18 complex, an effector mediating cellular response to ribosomal deficiency, which in turn activates JNK to trigger apoptosis and suppresses global translation through a mechanism independent of eIF2&#x3b1; phosphorylation and JNK. Our work establishes Ns1 as a critical regulator of ribosome biogenesis and cell survival in proliferating epithelia.