{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:43:01Z","timestamp":1785415381637,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011495","name":"Massachusetts Life Science Center","doi-asserted-by":"crossref","award":["GRT66675"],"award-info":[{"award-number":["GRT66675"]}],"id":[{"id":"10.13039\/100011495","id-type":"DOI","asserted-by":"crossref"}]},{"award":["GRT66675"],"award-info":[{"award-number":["GRT66675"]}],"id":[{"id":"https:\/\/ror.org\/033km2469","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007161","name":"Boston University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007161","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05qwgg493","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in these disorders. As increased TGFB expression has been implicated in major psychiatric diseases and lactic acid induces TGFB2 upregulation in metabolic diseases, we hypothesized that lactate-induced brain acidosis may drive widespread gene dysregulation through TGFB2 activation. In our previous microarray studies, increased TGFB2 expression was observed in postmortem brains of SCZ and BD patients, while pathway analyses suggested a key role for TGFB2 in the dysregulation of other genes, particularly astrocytic genes. TGFB2 itself also exhibited promoter DNA hypomethylation in postmortem brains of these patients. Here, while brain pH was lower in SCZ and BD patients, we investigated the effects of pH alteration on the expression and promoter DNA methylation of TGFB2 and TGFB2-correlated genes in iPSC-derived neurons, astrocytes, and brain organoids (brainoids). Cultures were treated with lactic acid, HCl, bicarbonate, or NaOH to alter culture medium pH by \u00b10.4 units, and gene expression and promoter DNA methylation were evaluated by qPCR analyses. In our reanalysis of postmortem brain microarray data, nearly 80% of dysregulated genes, together with TGFB2, exhibited inverse correlations with brain pH. Lactic acid treatment induced increased expression and promoter DNA hypomethylation of TGFB2 and several correlated genes in astrocytes and brainoids, whereas bicarbonate and NaOH treatments showed opposite effects. These findings suggest that lactate-mediated brain acidosis may contribute to TGFB2 upregulation and widespread gene dysregulation implicated in SCZ and BD pathogenesis. Therapeutic interventions targeting lactic acid accumulation or TGFB2 hyperexpression may mitigate disease-associated brain gene dysregulation.<\/jats:p>","DOI":"10.3390\/ijms27125456","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:31Z","timestamp":1781675791000},"page":"5456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate-Mediated Brain Acidosis Drives Epigenetic Dysregulation of TGFB2 and Associated Gene Networks in Schizophrenia and Bipolar Disorder"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8872-5174","authenticated-orcid":false,"given":"Hamid Mostafavi","family":"Abdolmaleky","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Stem Cells and Organoid Research Engineering (SCORE) Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Botson, MA 02215, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4944-7033","authenticated-orcid":false,"given":"Shabnam","family":"Nohesara","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reshma","family":"Subramonian","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"T.H. Chan School of Medicine, UMass Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kodhai","family":"Duraiarasan","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1093-6896","authenticated-orcid":false,"given":"Melissa","family":"Dorzin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Stem Cells and Organoid Research Engineering (SCORE) Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Botson, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Rong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6785-6370","authenticated-orcid":false,"given":"Giuseppe","family":"Pettinato","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Stem Cells and Organoid Research Engineering (SCORE) Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Botson, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5211-266X","authenticated-orcid":false,"given":"Sam","family":"Thiagalingam","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/epirev\/mxn001","article-title":"Schizophrenia: A concise overview of incidence, prevalence, and mortality","volume":"30","author":"McGrath","year":"2008","journal-title":"Epidemiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/S2215-0366(21)00501-0","article-title":"Relapse prevention in schizophrenia","volume":"9","author":"Jauhar","year":"2022","journal-title":"Lancet Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S2215-0366(24)00363-8","article-title":"The global epidemiology and health burden of the autism spectrum: Findings from the Global Burden of Disease Study 2021","volume":"12","author":"Santomauro","year":"2025","journal-title":"Lancet Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102294","DOI":"10.1016\/j.eclinm.2023.102294","article-title":"Life expectancy and years of potential life lost in people with mental disorders: A systematic review and meta-analysis","volume":"65","author":"Chan","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/S0140-6736(15)00241-X","article-title":"Bipolar disorder","volume":"387","author":"Grande","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.biopsych.2017.08.017","article-title":"Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register","volume":"83","author":"Hilker","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41380-019-0634-7","article-title":"The genetics of bipolar disorder","volume":"25","author":"Gordovez","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/jcpp.12499","article-title":"Heritability of autism spectrum disorders: A meta-analysis of twin studies","volume":"57","author":"Tick","year":"2016","journal-title":"J. Child Psychol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/nature08185","article-title":"Common polygenic variation contributes to risk of schizophrenia and bipolar disorder","volume":"460","author":"Purcell","year":"2009","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1038\/ng.2742","article-title":"Genome-wide association analysis identifies 13 new risk loci for schizophrenia","volume":"45","author":"Ripke","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41588-019-0344-8","article-title":"Identification of common genetic risk variants for autism spectrum disorder","volume":"51","author":"Grove","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/wps.20309","article-title":"Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: A systematic review and large scale meta-analysis","volume":"15","author":"Vancampfort","year":"2016","journal-title":"World Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1001\/jamapediatrics.2022.5629","article-title":"Association between autism spectrum disorders and cardiometabolic diseases: A systematic review and meta-analysis","volume":"177","author":"Dhanasekara","year":"2023","journal-title":"JAMA Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nohesara, S., Abdolmaleky, H.M., and Thiagalingam, S. (2023). Epigenetic aberrations in major psychiatric diseases related to diet and gut microbiome alterations. Genes, 14.","DOI":"10.3390\/genes14071506"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mostafavi, S., Nohesara, S., Pirani, A., Mostafavi Abdolmaleky, H., and Thiagalingam, S. (2025). Oral\u2013Gut Microbiota Crosstalk and Epigenetic Targets in Metabolic and Neuropsychiatric Diseases. Nutrients, 17.","DOI":"10.3390\/nu17213367"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ijdevneu.2010.08.007","article-title":"Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia","volume":"29","author":"Clay","year":"2011","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.2217\/epi-2021-0074","article-title":"Cataloging recent advances in epigenetic alterations in major mental disorders and autism","volume":"13","author":"Abdolmaleky","year":"2021","journal-title":"Epigenomics"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Abdolmaleky, H.M., Martin, M., Zhou, J.-R., and Thiagalingam, S. (2023). Epigenetic alterations of brain non-neuronal cells in major mental diseases. Genes, 14.","DOI":"10.3390\/genes14040896"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neubiorev.2014.11.005","article-title":"Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications","volume":"48","author":"Rajasekaran","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1091\/mbc.e09-10-0874","article-title":"Mitochondrial fragmentation leads to intracellular acidification in Caenorhabditis elegans and mammalian cells","volume":"21","author":"Johnson","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/sj.ki.5002632","article-title":"Measurement of cytosolic and mitochondrial pH in living cells during reversible metabolic inhibition","volume":"73","author":"Balut","year":"2008","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nohesara, S., Abdolmaleky, H.M., and Thiagalingam, S. (2024). Potential for new therapeutic approaches by targeting lactate and pH mediated epigenetic dysregulation in major mental diseases. Biomedicines, 12.","DOI":"10.3390\/biomedicines12020457"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e967","DOI":"10.1038\/tp.2016.239","article-title":"Elevated brain lactate in schizophrenia: A 7 T magnetic resonance spectroscopy study","volume":"6","author":"Rowland","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/npp.2017.167","article-title":"Decreased brain pH as a shared endophenotype of psychiatric disorders","volume":"43","author":"Hagihara","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41398-023-02336-2","article-title":"Altered distribution and localization of organellar Na+\/H+ exchangers in postmortem schizophrenia dorsolateral prefrontal cortex","volume":"13","author":"Pruett","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1365-2990.2008.01003a.x","article-title":"pH measurement as quality control on human post mortem brain tissue: A study of the BrainNet Europe consortium","volume":"35","author":"Monoranu","year":"2009","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0169-328X(03)00337-1","article-title":"Quantifying mRNA in postmortem human brain: Influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance","volume":"118","author":"Preece","year":"2003","journal-title":"Mol. Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"RP89376","DOI":"10.7554\/eLife.89376.3","article-title":"Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment","volume":"12","author":"Hagihara","year":"2024","journal-title":"Elife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1038\/s41467-020-18756-3","article-title":"Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle","volume":"11","author":"Theparambil","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s42255-018-0030-7","article-title":"TGF-\u03b22 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism","volume":"1","author":"Takahashi","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1002\/ajmg.b.32691","article-title":"Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality\/asymmetry in schizophrenia and bipolar disorder","volume":"180","author":"Abdolmaleky","year":"2019","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.biopsych.2011.04.013","article-title":"Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects","volume":"70","author":"Miller","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.neuroscience.2010.01.016","article-title":"A cross-laboratory comparison of expression profiling data from normal human postmortem brain","volume":"167","author":"Mistry","year":"2010","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hagihara, H., Murano, T., and Miyakawa, T. (2023). The gene expression patterns as surrogate indices of pH in the brain. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1151480"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/s41586-023-06409-6","article-title":"Lactate limits CNS autoimmunity by stabilizing HIF-1\u03b1 in dendritic cells","volume":"620","author":"Sanmarco","year":"2023","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3419034","DOI":"10.1155\/2020\/3419034","article-title":"D-lactic acid as a metabolite: Toxicology, diagnosis, and detection","volume":"2020","author":"Pohanka","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.ccr.2010.11.015","article-title":"Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation","volume":"18","author":"Figueroa","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrg2485","article-title":"The many roles of histone deacetylases in development and physiology: Implications for disease and therapy","volume":"10","author":"Haberland","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2007.02.005","article-title":"Chromatin modifications and their function","volume":"128","author":"Kouzarides","year":"2007","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1172\/JCI58644","article-title":"Innate immunity in the central nervous system","volume":"122","author":"Ransohoff","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/ajmg.b.32361","article-title":"Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and psychotic bipolar disorder","volume":"168","author":"Abdolmaleky","year":"2015","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Mostafavi Abdolmaleky, H., Alam, R., Nohesara, S., Deth, R.C., and Zhou, J.-R. (2024). iPSC-derived astrocytes and neurons replicate brain gene expression, epigenetic, cell morphology and connectivity alterations found in Autism. Cells, 13.","DOI":"10.3390\/cells13131095"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1016\/j.stem.2021.07.010","article-title":"Human brain organoids assemble functionally integrated bilateral optic vesicles","volume":"28","author":"Gabriel","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7402","DOI":"10.1038\/srep07402","article-title":"Formation of well-defined embryoid bodies from dissociated human induced pluripotent stem cells using microfabricated cell-repellent microwell arrays","volume":"4","author":"Pettinato","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.cell.2011.03.022","article-title":"Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain","volume":"145","author":"Guo","year":"2011","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1101\/gr.126417.111","article-title":"Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes","volume":"22","author":"Nestor","year":"2012","journal-title":"Genome Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3892\/ijmm.2025.5682","article-title":"Histone lactylation: Unveiling a novel pathway for the impact of lactate on physiological and pathological processes","volume":"57","author":"Jian","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.mito.2020.11.009","article-title":"Mitochondrial dysfunction in schizophrenia: With a focus on postmortem studies","volume":"56","author":"Roberts","year":"2021","journal-title":"Mitochondrion"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:49:47Z","timestamp":1781844587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125456"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]}}}