Molecular Psychiatry最新文献

{"title":"Longitudinal multi-omics analysis of umbilical cord blood and childhood serum in Autism.","authors":"Aisling Noone, Kirsten Dowling, Daragh O'Boyle, Michael Carter, Anna V Golubeva, Caitriona Scaife, Bodil H Bech, Tine B Henriksen, Louise Gallagher, Catherine Mooney, Ali S Khashan, Deirdre M Murray, Jane A English","doi":"10.1038/s41380-025-03157-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03157-z","url":null,"abstract":"<p><p>There is considerable evidence implicating maternal immune activation (MIA) and cytokine dysregulation in the pathophysiology of Autism. However, cytokines, due to their lack of specificity are unlikely to translate clinically as prognostic biomarkers. Our aim was to explore the perinatal molecular pathways dysregulated in umbilical cord blood, which precede a diagnosis of childhood Autism, and ascertain whether these putative biomarkers persisted into pre-pubertal childhood. In a cohort of 2137 mother-infant dyads, we conducted a nested case-control study in the BASELINE Birth Cohort. Proteomic and metabolomic analysis was performed on cord blood plasma from 22 children diagnosed with Autism before age 5, and 44 neurotypical controls. In a clinical diagnostic follow-up between 7-10 years in the PiRAMiD Cohort, 24 children with Autism and 48 controls provided blood samples for molecular profiling. In cord blood, proteomics revealed altered glycolysis, selenium metabolism, oxygen transport, and complement signalling. Alterations in these protein pathways persisted into childhood, and dysregulation of GAPDH, SELENBP1, and BLVRB proteins were evident in both cord blood and in serum from pre-pubertal children with Autism. In cord blood, metabolomics analysis indicated Autism outcome was associated with reduced levels of circulating steroids and increased sulfate. We confirmed androstenedione was reduced in cord blood, in Autism cases in comparison to controls, however changes in androstenedione levels were not evident in serum from pre-pubertal children with Autism. Our findings were further corroborated using machine learning approaches, with an AUROC ranging from 0.82 to 0.85 for proteomic and metabolomic cord blood prediction models, respectively. Collectively, these findings confirm a cord blood molecular signature precedes the onset of Autism and has the potential to lead to prognostic biomarkers. Our integrative multi-omics analysis reveals materno-feto-placental molecular processes which potentially underpin Autism aetiology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study.","authors":"Lani Cupo, Haley A Vecchiarelli, Daniel Gallino, Jared VanderZwaag, Katerina Bradshaw, Annie Phan, Mohammadparsa Khakpour, Benneth Ben-Azu, Elisa Guma, Jérémie P Fouquet, Shoshana Spring, Brian J Nieman, Gabriel A Devenyi, Marie-Eve Tremblay, M Mallar Chakravarty","doi":"10.1038/s41380-025-03189-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03189-5","url":null,"abstract":"<p><p>While cannabis use during pregnancy is often perceived as harmless, little is known about its consequences on offspring neurodevelopment. There is an urgent need to map the effects of prenatal cannabis exposure on the brain through the course of the lifespan. We used magnetic resonance imaging spanning nine timepoints, behavioral assays, and electron microscopy to build a trajectory from gestation to adulthood in mice exposed prenatally to delta-9-tetrahydrocannabinol (THC). Our results demonstrate a spatio-temporal patterning, with ventriculomegaly in THC-exposed embryos followed by a deceleration of brain growth in neonates that is sustained until adulthood, especially in females. We observed consistently impacted regions in both the cortex and subcortex, aligned with sex-dependent changes to social behavior in neonates and increased anxiety-like behavior in adolescents. Our results suggest prenatal THC exposure has a sustained sex-dependent impact on neurodevelopment that may persist into early adulthood.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons.","authors":"Xiao Su, Hanwen Zhang, Yan Hong, Qian Yang, Le Wang, Tiffany Le, Jiayi Liu, Lasya Cheruvu, Emily Labour, Siwei Zhang, Karla Mendez-Maldonado, Anat Kreimer, Hongjun Song, Guo-Li Ming, Jubao Duan, Zhiping P Pang","doi":"10.1038/s41380-025-03246-z","DOIUrl":"10.1038/s41380-025-03246-z","url":null,"abstract":"<p><p>Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with both common risk variants of small effect sizes and rare risk variants of high penetrance. Rare premature open reading frame (ORF) termination variants in SETD1A (SET Domain Containing 1A) show a strong association with SCZ; however, it remains largely unclear how rare premature ORF termination variants in SETD1A contribute to the pathophysiology of SCZ. To understand the impact of SETD1A rare premature ORF termination variants in human neurons, we CRISPR/Cas9-engineered five isogenic pairs of human induced pluripotent stem cells (iPSCs), with a recurrent heterozygous patient-specific premature ORF termination mutation c.4582-2delAG in two donor lines and a heterozygous frameshift mutation c.4596_4597insG (p. Leu1533fs) in three donor lines. These two mutations are predicted to cause a premature stop codon in exon 16 of SETD1A, leading to SETD1A haploinsufficiency. We found that these presumably loss-of-function (LoF) mutations caused the SETD1A mRNAs to be degraded by nonsense-mediated decay (NMD), accompanied by a reduction of full-length SETD1A protein level in iPSCs. We then characterized the morphological, electrophysiological, and transcriptomic impacts of SETD1A^+/- LoF mutations in iPSC-derived human excitatory neurons induced by NGN2. We found that the SETD1A^+/- exon-16 LoF mutations altered dendrite complexity, dysregulated synaptic transmission, and synaptic plasticity, likely by dysregulating genes involved in synaptic function. These results provide mechanistic insights into how SETD1A^+/- exon-16 patient-specific LoF mutations affect neuron phenotypes that may be relevant to the pathophysiology of SCZ.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into taxane-induced psychiatric adverse events: a global pharmacovigilance and experimental investigation","authors":"Anqi Lin, Yiyin Mai, Guichuan Lai, Zhengrui Li, Junyi Shen, Hank Z. H. Wong, Nan Zhang, Jian Zhang, Kailai Li, Quan Cheng, Bicheng Ye, Aimin Jiang, Peng Luo, Guiqing Jia, Qunqing Chen","doi":"10.1038/s41380-025-03252-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03252-1","url":null,"abstract":"<p>Taxane drugs are essential chemotherapeutic agents in the clinical management of various solid tumors; however, their associated psychiatric adverse effects and underlying mechanisms remain insufficiently explored. This study aims to assess the association between taxane drugs and psychiatric adverse events (pAEs) and to investigate their potential biological mechanisms. The association between taxane drugs and pAEs was analyzed using the reporting odds ratio (ROR) method based on data from the Food and Drug Administration Adverse Event Reporting System (FAERS) (2013–2023) and the World Health Organization’s global pharmacovigilance database (Vigibase database). Tumor-bearing mouse models treated with taxane drugs were developed, and RNA sequencing was conducted to examine the underlying molecular mechanisms. Single-sample gene set enrichment analysis (ssGSEA) was performed to evaluate the activity of relevant pathways. A total of 10,132 cases and 10,525 cases of pAEs associated with taxane drugs were identified in the FAERS and Vigibase databases, respectively. Nine significant taxane-related psychiatric adverse events (TX-related pAEs) were identified, with emotional distress showing the strongest signal. Subgroup analysis indicated that women (ROR_FAERS = 15.244), individuals younger than 45 years (ROR_FAERS = 17.849), and breast cancer patients exhibited a higher risk. Mechanistic studies revealed four significantly associated signaling pathways: cobalamin metabolic process, regulation of response to oxidative stress, G protein-coupled receptor signaling, and nitric oxide-mediated signal transduction. This study is the first to systematically assess taxane drug-associated pAEs, elucidating the characteristics of high-risk populations and underlying molecular mechanisms, thereby offering valuable insights for clinical drug safety and personalized treatment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"84 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging reduces motivation through decreased Bdnf expression in the ventral tegmental area","authors":"Hanyue Cecilia Lei, Kyle E. Parker, Chao-Cheng Kuo, Carla M. Yuede, Jordan G. McCall, Shin-ichiro Imai","doi":"10.1038/s41380-025-03253-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03253-0","url":null,"abstract":"<p>Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor in aged populations, to those of aging. We found that both social isolation and aging decreased motivation in mice, but that <i>Bdnf</i> expression in the ventral tegmental area (VTA) was selectively decreased during aging. Furthermore, VTA-specific <i>Bdnf</i> knockdown in young mice recapitulated reduced motivation observed in old mice. These results demonstrate that maintaining <i>Bdnf</i> expression in the VTA could promote motivation to engage in effortful activities and potentially prevent age-associated neuropsychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"67 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxytocin attenuates the retrieval of methamphetamine-associated reward memories by enhancing adult hippocampal neurogenesis in mice","authors":"Jialing Cai, Xiaohang Che, Yanling Deng, Zhenkun Guo, Meixue Yin, Yuting Li, Xincheng Li, Xiaoling Liu, Yuanchao Luo, Tianyu Xu, Wenzhe Zhu, Nina An, Yijun Bai, Chunfu Wu, Jingyu Yang","doi":"10.1038/s41380-025-03222-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03222-7","url":null,"abstract":"<p>The present study was designated to investigate the effect of oxytocin (OXT) on the retrieval of methamphetamine (METH)-associated reward memories induced by drugs in mice and its underlying mechanisms related to adult hippocampal neurogenesis (AHN) and memory engrams. The data showed that repeated hippocampal microinjections of OXT (1.25 and 2.5 μg) for 8 consecutive days significantly prevented the retrieval of METH-associated reward memories induced by drugs in a time-, dose- and receptor-dependent manner in mice. At the meanwhile, OXT was found to markedly elevate AHN levels, enhancing the proliferation, survival and maturation of newborn neurons by using NestinCreER^T2::Rosa26-<i>td</i>Tomato mice and BrdU labeling. Notably, reduction or depletion of AHN by temozolomide (TMZ) or NestinCreER^T2 mice combined with adeno-associated viruses (AAVs) (AAV-CAG-DIO-rtTA-EGFP and AAV-TRE-DTA) could attenuate the inhibition of OXT on the retrieval of METH-associated reward memories in mice. By using activity-dependent labeling strategy in mice, it was observed that the retrieval of METH-associated reward memories was mediated by activation of METH-associated memory engrams in the dentate gyrus (DG) region of the hippocampus. Repeated hippocampal microinjections of OXT effectively prevented the activation of these memory engrams, which could be abolished after reducing AHN by TMZ. In summary, this study revealed that OXT effectively prevented the retrieval of METH-associated reward memories induced by drugs in mice, which may be related to its enhancement on AHN as well as inhibition on METH-associated memory engrams in DG.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"3 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained antidepressant actions of ketamine involve TAMM41-mediated transfer of astrocytic sigma-1 receptor to neuron.","authors":"Lin Guo, Xinting Lin, Qinghua Wang, Ziyu Liu, Siyu Liu, Na Lv, Zhidong Liu, Yinan Wang, Congcong Sun, Yun Wang","doi":"10.1038/s41380-025-03248-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03248-x","url":null,"abstract":"<p><p>Several limitations such as delayed onset and insufficient efficacy exist in current antidepressant treatments, thereby driving the search for new therapeutic approaches. Ketamine produces a rapid and sustained antidepressant response, yet its molecular mechanisms remain elusive. Here, we elucidated that the transfer of sigma-1 receptor (S1R) from astrocytes to neurons was associated with ketamine's antidepressant effect. Mechanistically, we identified that ketamine activated the mitochondrial protein TAMM41 and then facilitated the transfer of astrocytic S1R via the TAMM41-cardiolipin-exosomes axis. Furthermore, conditional deletion of astrocytic TAMM41 exhibited depressive-like behaviors and abolished the sustained antidepressant effect of ketamine. Inspired by these findings of endogenous exosomes delivering S1R, we devised a strategy to engineer exosome-encapsulated S1R (S1R-EXOs) using exosomes released by human red blood cells and synthetic S1R mRNA. We found that exogenous S1R-EXOs effectively delivered S1R to neurons in S1R knockout mice. Finally, we verified that exogenous S1R-EXOs produced antidepressant-like effect. Our findings reveal that astrocytic TAMM41 underlies the sustained antidepressant effect of ketamine through exosomal delivery of S1R to neurons, offering potential for new strategies in depression treatment. Considering the advantages of human red blood cells and therapeutic mRNA, our results also provide a promising avenue that warrants further translational and clinical exploration.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-life inflammation increases aggressive behavior in adult male mice through an astrocyte-neuron signaling","authors":"Jiabei Wang, Jianhao Wang, Hongyu Chen, Feng Gao, Ruifeng Xu, Yida Lv, Shuai Ding, Fang Li, Xiang Li, Yuke Shi, Hangyu Wei, Xinzhuo Chen, Junqin Zhao, Jing Xiong, Xuejie Li, Liang Zhao, Qing-tao Meng, Xuan Xiao, Zhi-Hao Wang","doi":"10.1038/s41380-025-03260-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03260-1","url":null,"abstract":"<p>Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of <i>Dnm1l</i>, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"48 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors","authors":"Tyler G. Ekins, Chloe Rybicki-Kler, Tao Deng, Isla A. W. Brooks, Izabela Jedrasiak-Cape, Ethan Donoho, Omar J. Ahmed","doi":"10.1038/s41380-025-03257-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03257-w","url":null,"abstract":"<p>Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT_2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) – important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer’s disease – lack 5-HT_2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT_2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT_2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer’s disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT_2A receptors.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-epigenome-wide analyses and meta-analysis of child maltreatment in judicial autopsies and intervened children and adolescents.","authors":"Shota Nishitani, Takashi X Fujisawa, Shinichiro Takiguchi, Akiko Yao, Kazuhiro Murata, Daiki Hiraoka, Yoshifumi Mizuno, Keiko Ochiai, Natasha Y S Kawata, Kai Makita, Daisuke N Saito, Sakae Mizushima, Shizuka Suzuki, Sawa Kurata, Naoki Ishiuchi, Daiki Taniyama, Naoki Nakao, Akira Namera, Hidehiko Okazawa, Masataka Nagao, Akemi Tomoda","doi":"10.1038/s41380-025-03236-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03236-1","url":null,"abstract":"<p><p>Child maltreatment (CM) is associated with adverse physical, psychological, and neurodevelopmental outcomes later in life. Epigenetic modifications, particularly DNA methylation, have been proposed as potential mechanisms underlying these long-term effects. To identify robust CM-associated methylation signatures, we conducted epigenome-wide analyses across three independent cohorts: judicial autopsy cases (CM:11, Controls:7), toddlers shortly after social intervention (CM:36, Controls:49), and adolescents who underwent brain MRI (CM:61, Controls:62). Each cohort was analyzed separately, followed by a meta-analysis to identify common methylation sites associated with CM exposure. The meta-analysis identified four significant CpG sites located within the ATE1, SERPINB9P1, CHST11, and FOXP1 genes. Among these, methylation of FOXP1 was consistently associated with structural brain alterations, including increased gray matter volume (GMV) in the orbitofrontal cortex (OFrC) and middle/posterior cingulate gyrus (MPCG), and decreased GMV in the occipital fusiform gyrus (OFuG). These brain regions are implicated in emotional regulation, memory retrieval, and social cognition, suggesting a potential neurobiological mechanism linking CM to later psychopathology. Furthermore, methylation risk scores (MRS) derived from these four CpGs successfully discriminated individuals who experienced early-life adversity in an independent validation dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.672, highlighting their potential utility as biomarkers. Gene ontology and pathway analyses revealed enrichment of cholinergic and glutamatergic synaptic transmission pathways, supporting their involvement in traumatic memory formation. Our findings provide novel insights into the epigenetic mechanisms underlying CM and identify potential biomarkers for early detection, prevention, and therapeutic intervention, ultimately contributing to breaking the intergenerational cycle of maltreatment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}