{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:11Z","timestamp":1787028551098,"version":"build-2736575974"},"reference-count":92,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["721236-TREATMENT"],"award-info":[{"award-number":["721236-TREATMENT"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["PID2021-122765OB-I00"],"award-info":[{"award-number":["PID2021-122765OB-I00"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["EIC-2023-PATFINDERCHALLENGES-01-3"],"award-info":[{"award-number":["EIC-2023-PATFINDERCHALLENGES-01-3"]}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency (ARIS)","doi-asserted-by":"publisher","award":["721236-TREATMENT"],"award-info":[{"award-number":["721236-TREATMENT"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency (ARIS)","doi-asserted-by":"publisher","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency (ARIS)","doi-asserted-by":"publisher","award":["PID2021-122765OB-I00"],"award-info":[{"award-number":["PID2021-122765OB-I00"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency (ARIS)","doi-asserted-by":"publisher","award":["EIC-2023-PATFINDERCHALLENGES-01-3"],"award-info":[{"award-number":["EIC-2023-PATFINDERCHALLENGES-01-3"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish Ministry of Science Innovation and Universities (MCIU), Agencia Estatal de Investigaci\u00f3n (AEI)","doi-asserted-by":"publisher","award":["721236-TREATMENT"],"award-info":[{"award-number":["721236-TREATMENT"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish Ministry of Science Innovation and Universities (MCIU), Agencia Estatal de Investigaci\u00f3n (AEI)","doi-asserted-by":"publisher","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish Ministry of Science Innovation and Universities (MCIU), Agencia Estatal de Investigaci\u00f3n (AEI)","doi-asserted-by":"publisher","award":["PID2021-122765OB-I00"],"award-info":[{"award-number":["PID2021-122765OB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish Ministry of Science Innovation and Universities (MCIU), Agencia Estatal de Investigaci\u00f3n (AEI)","doi-asserted-by":"publisher","award":["EIC-2023-PATFINDERCHALLENGES-01-3"],"award-info":[{"award-number":["EIC-2023-PATFINDERCHALLENGES-01-3"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Horizon Europe Program","award":["721236-TREATMENT"],"award-info":[{"award-number":["721236-TREATMENT"]}]},{"name":"Horizon Europe Program","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}]},{"name":"Horizon Europe Program","award":["PID2021-122765OB-I00"],"award-info":[{"award-number":["PID2021-122765OB-I00"]}]},{"name":"Horizon Europe Program","award":["EIC-2023-PATFINDERCHALLENGES-01-3"],"award-info":[{"award-number":["EIC-2023-PATFINDERCHALLENGES-01-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H2O2-induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H2O2. Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H2O2, contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H2O2, whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O2\u2022-, a known desensitizing factor. The physiological relevance of O2\u2022- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H2O2, possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms252011119","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T10:11:04Z","timestamp":1729073464000},"page":"11119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aripiprazole, but Not Olanzapine, Alters the Response to Oxidative Stress in Fao Cells by Reducing the Activation of Mitogen-Activated Protein Kinases (MAPKs) and Promoting Cell Survival"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-5462","authenticated-orcid":false,"given":"Barbara","family":"Kramar","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinkara","family":"Pirc Marolt","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-523X","authenticated-orcid":false,"given":"Ayse Mine","family":"Yilmaz Goler","sequence":"additional","affiliation":[{"name":"Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854 Istanbul, Turkey"},{"name":"Department of Biochemistry, School of Medicine, Marmara University, 34854 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4031-7267","authenticated-orcid":false,"given":"Du\u0161an","family":"\u0160uput","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6948-7238","authenticated-orcid":false,"given":"Irina","family":"Milisav","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia"},{"name":"Laboratory of Oxidative Stress Research, Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2796-1453","authenticated-orcid":false,"given":"Mar\u00eda","family":"Monsalve","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Sols-Morreale (CSIC-UAM), Arturo Duperier, 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.euroneuro.2018.04.005","article-title":"Psychotropic drugs use and psychotropic polypharmacy among persons with Alzheimer\u2019s disease","volume":"28","author":"Orsel","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.jaac.2016.03.012","article-title":"Antipsychotic Use Trends in Youth with Autism Spectrum Disorder and\/or Intellectual Disability: A Meta-Analysis","volume":"55","author":"Park","year":"2016","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e197850","DOI":"10.1001\/jamanetworkopen.2019.7850","article-title":"Antipsychotic Treatment Among Youths with Attention-Deficit\/Hyperactivity Disorder","volume":"2","author":"Sultan","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dennis, J.A., Gittner, L.S., Payne, J.D., and Nugent, K. (2020). Characteristics of U.S. adults taking prescription antipsychotic medications, National Health and Nutrition Examination Survey 2013\u20132018. BMC Psychiatry, 20.","DOI":"10.1186\/s12888-020-02895-4"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1017\/S2045796020000293","article-title":"Use of antipsychotics in children and adolescents: A picture from the ARITMO population-based European cohort study","volume":"29","author":"Kaguelidou","year":"2020","journal-title":"Epidemiol. Psychiatr. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.2165\/00003088-199937030-00001","article-title":"Olanzapine","volume":"37","author":"Callaghan","year":"1999","journal-title":"Clin. Pharmacokinet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s40262-018-0664-3","article-title":"Clinical Pharmacokinetics of Atypical Antipsychotics: An Update","volume":"57","author":"Mauri","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Carli, M., Kolachalam, S., Longoni, B., Pintaudi, A., Baldini, M., Aringhieri, S., Fasciani, I., Annibale, P., Maggio, R., and Scarselli, M. (2021). Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030238"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chow, R.T.S., Whiting, D., Favril, L., Ostinelli, E., Cipriani, A., and Fazel, S. (2023). An umbrella review of adverse effects associated with antipsychotic medications: The need for complementary study designs. Neurosci. Biobehav. Rev., 155.","DOI":"10.1016\/j.neubiorev.2023.105454"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/schbul\/sbad126","article-title":"Antipsychotic Medication and Risk of Metabolic Disorders in People with Schizophrenia: A Longitudinal Study Using the UK Clinical Practice Research Datalink","volume":"50","author":"Eyles","year":"2024","journal-title":"Schizophr. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Grajales, D., Ferreira, V., and Valverde, \u00c1.M. (2019). Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain. Cells, 8.","DOI":"10.3390\/cells8111336"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1007\/s12325-021-01689-8","article-title":"Real-World Data on the Adverse Metabolic Effects of Second-Generation Antipsychotics and Their Potential Determinants in Adult Patients: A Systematic Review of Population-Based Studies","volume":"38","author":"Bernardo","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.euroneuro.2019.12.118","article-title":"Long-term metabolic and cardiovascular effects of antipsychotic drugs. A meta-analysis of randomized controlled trials","volume":"32","author":"Rotella","year":"2020","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.2174\/1381612827666210804110139","article-title":"Metabolomic Connections between Schizophrenia, Antipsychotic Drugs and Metabolic Syndrome: A Variety of Players","volume":"27","author":"Molina","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"736","DOI":"10.5498\/wjp.v11.i10.736","article-title":"Antipsychotics cardiotoxicity: What\u2019s known and what\u2019s next","volume":"11","author":"Li","year":"2021","journal-title":"World J. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mukherjee, S., Skrede, S., Milbank, E., Andriantsitohaina, R., L\u00f3pez, M., and Fern\u00f8, J. (2022). Understanding the Effects of Antipsychotics on Appetite Control. Front. Nutr., 8.","DOI":"10.3389\/fnut.2021.815456"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Papatriantafyllou, E., Efthymiou, D., Markopoulou, M., Sakellariou, E.-M., and Vassilopoulou, E. (2022). The Effects of Use of Long-Term Second-Generation Antipsychotics on Liver and Kidney Function: A Prospective Study. Diseases, 10.","DOI":"10.3390\/diseases10030048"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s00204-020-02963-4","article-title":"Antidepressants- and antipsychotics-induced hepatotoxicity","volume":"95","year":"2021","journal-title":"Arch. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mortimer, K.R.H., Katshu, M.Z.U.H., and Chakrabarti, L. (2023). Second-generation antipsychotics and metabolic syndrome: A role for mitochondria. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1257460"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rosell-Hidalgo, A., Eakins, J., Walker, P., Moore, A.L., and Ghafourian, T. (2023). Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays. Biomedicines, 11.","DOI":"10.3390\/biomedicines11123272"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1146\/annurev-clinpsy-082719-104030","article-title":"Stress and Psychiatric Disorders: The Role of Mitochondria","volume":"16","author":"Daniels","year":"2020","journal-title":"Annu. Rev. Clin. Psychol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2022.10.002","article-title":"Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells","volume":"69","author":"Trigo","year":"2023","journal-title":"Mitochondrion"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Doblado, L., Lueck, C., Rey, C., Samhan-Arias, A.K., Prieto, I., Stacchiotti, A., and Monsalve, M. (2021). Mitophagy in Human Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083903"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41556-022-00843-w","article-title":"Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance","volume":"24","author":"Romani","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.01.026","article-title":"PGC-1\u03b1 regulates the mitochondrial antioxidant defense system in vascular endothelial cells","volume":"66","author":"Valle","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s10456-016-9502-0","article-title":"Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1\u03b1-deficient mice","volume":"19","author":"Prieto","year":"2016","journal-title":"Angiogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Li, H., Peng, S., Li, S., Liu, S., Lv, Y., Yang, N., Yu, L., Deng, Y.-H., Zhang, Z., and Fang, M. (2019). Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-36930-y"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0140-6736(19)31135-3","article-title":"Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: A systematic review and network meta-analysis","volume":"394","author":"Huhn","year":"2019","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.2147\/NDT.S209284","article-title":"A commentary on the efficacy of olanzapine for the treatment of schizophrenia: The past, present, and future","volume":"15","author":"Citrome","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Alabaku, O., Yang, A., Tharmarajah, S., Suda, K., Vigod, S., and Tadrous, M. (2023). Global trends in antidepressant, atypical antipsychotic, and benzodiazepine use: A cross-sectional analysis of 64 countries. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0284389"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1093\/ajhp\/55.10.1003","article-title":"Olanzapine: A serotonin-dopamine-receptor antagonist for antipsychotic therapy","volume":"55","author":"Bever","year":"1998","journal-title":"Am. J. Health-Syst. Pharm."},{"key":"ref_32","first-page":"CD006654","article-title":"Olanzapine versus other atypical antipsychotics for schizophrenia","volume":"17","author":"Komossa","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.2217\/pgs.13.120","article-title":"Pharmacogenetics of olanzapine metabolism","volume":"14","author":"Dahl","year":"2013","journal-title":"Pharmacogenomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113757","DOI":"10.1016\/j.fct.2023.113757","article-title":"Olanzapine-induced nonalcoholic fatty liver disease: The effects of differential food pattern and the involvement of PGRMC1 signaling","volume":"176","author":"Zhu","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Del Campo, A., Bustos, C., Mascayano, C., Acu\u00f1a-Castillo, C., Troncoso, R., and Rojo, L.E. (2018). Metabolic Syndrome and Antipsychotics: The Role of Mitochondrial Fission\/Fusion Imbalance. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00144"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.euroneuro.2018.01.004","article-title":"Second generation antipsychotic-induced mitochondrial alterations: Implications for increased risk of metabolic syndrome in patients with schizophrenia","volume":"28","author":"Scaini","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3109\/00498254.2015.1078522","article-title":"Involvement of oxidative stress and mitochondrial\/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes","volume":"46","author":"Eftekhari","year":"2016","journal-title":"Xenobiotica"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pirc Marolt, T., Kramar, B., Vovk, A., Podgornik, H., \u0160uput, D., and Milisav, I. (2023). Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis. Antioxidants, 12.","DOI":"10.3390\/antiox12111930"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00210-019-01665-8","article-title":"In vitro effects of antipsychotics on mitochondrial respiration","volume":"392","author":"Bakhouche","year":"2019","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1192\/bjp.186.1.7","article-title":"Partial agonism and schizophrenia","volume":"186","author":"Bolonna","year":"2005","journal-title":"Br. J. Psychiatry"},{"key":"ref_41","first-page":"779","article-title":"Aripiprazole","volume":"16","author":"McGavin","year":"2002","journal-title":"Mol. Diagn. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1007\/s40262-021-01041-x","article-title":"Influence of CYP2D6 Phenotypes on the Pharmacokinetics of Aripiprazole and Dehydro-Aripiprazole Using a Physiologically Based Pharmacokinetic Approach","volume":"60","author":"Kneller","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"ref_43","unstructured":"(2012). Aripiprazole. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, National Institute of Diabetes and Digestive and Kidney Diseases."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1000201","DOI":"10.4172\/2329-6887.1000201","article-title":"Acute Drug-Induced Hepatitis during Aripiprazole Monotherapy: A Case Report","volume":"4","author":"Kornischka","year":"2016","journal-title":"J. Pharmacovigil."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gao, Y., Wu, C., Zhai, X., Niu, M., Bai, Z., Song, H., Zhao, X., Wang, J., and Xiao, X. (2023). Aripiprazole-induced liver injury: A spontaneous reporting database study. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1226386"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hardy, R.E., Chung, I., Yu, Y., Loh, S.H.Y., Morone, N., Soleilhavoup, C., Travaglio, M., Serreli, R., Panman, L., and Cain, K. (2023). The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors. Biol. Direct, 18.","DOI":"10.1186\/s13062-023-00375-9"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kramar, B., Pirc Marolt, T., Monsalve, M., \u0160uput, D., and Milisav, I. (2022). Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158292"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.schres.2022.07.007","article-title":"Prevalence of metabolic syndrome and related factors in a large sample of antipsychotic na\u00efve patients with first-episode psychosis: Baseline results from the PAFIP cohort","volume":"246","author":"Alameda","year":"2022","journal-title":"Schizophr. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8881770","DOI":"10.1155\/2021\/8881770","article-title":"Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives","volume":"2021","author":"Ermakov","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.biopsych.2018.02.1175","article-title":"A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia","volume":"83","author":"Cappi","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0014-4827(87)90113-3","article-title":"The Fao Cell. A tissue culture model for lipoprotein synthesis and secretion: II. Modulation by lipid depletion and supplementation","volume":"170","author":"Scarino","year":"1987","journal-title":"Exp. Cell Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1242\/jcs.104.2.307","article-title":"Non-genotoxic hepatocarcinogenesis in vitro: The FaO hepatoma line responds to peroxisome proliferators and retains the ability to undergo apoptosis","volume":"104","author":"Bayly","year":"1993","journal-title":"J. Cell Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1089\/ars.2010.3643","article-title":"PGC-1\u03b1 Regulates Translocated in Liposarcoma Activity: Role in Oxidative Stress Gene Expression","volume":"15","author":"Tierrez","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-0043-116492","article-title":"Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017","volume":"51","author":"Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hammad, M., Raftari, M., Ces\u00e1rio, R., Salma, R., Godoy, P., Emami, S.N., and Haghdoost, S. (2023). Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells: A Possible General Mechanism of Resistance to Therapy. Antioxidants, 12.","DOI":"10.3390\/antiox12071371"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Pirc Marolt, T., Kramar, B., Rozman, K.B., \u0160uput, D., and Milisav, I. (2020). Aripiprazole reduces liver cell division. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240754"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41420-021-00579-w","article-title":"Ferroptosis: A cell death connecting oxidative stress, inflammation and cardiovascular diseases","volume":"7","author":"Yu","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/cdd.2017.186","article-title":"BCL-2 family proteins: Changing partners in the dance towards death","volume":"25","author":"Kale","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1023\/A:1014318615955","article-title":"Cell death regulation by the mammalian IAP antagonist Diablo\/Smac","volume":"7","author":"Verhagen","year":"2002","journal-title":"Apoptosis"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.bbamcr.2010.12.012","article-title":"The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation","volume":"1813","author":"Plotnikov","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"653","DOI":"10.12688\/f1000research.22092.1","article-title":"An overview of mammalian p38 mitogen-activated protein kinases, central regulators of cell stress and receptor signaling","volume":"9","author":"Han","year":"2020","journal-title":"F1000Research"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/S1357-2725(01)00093-0","article-title":"The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs)","volume":"33","author":"Barr","year":"2001","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1089\/ars.2010.3733","article-title":"Mitogen-Activated Protein Kinases in Mammalian Oxidative Stress Responses","volume":"15","author":"Runchel","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"17580","DOI":"10.1074\/jbc.274.25.17580","article-title":"Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes","volume":"274","author":"Carballo","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.bbrc.2009.05.051","article-title":"STAT3 deletion sensitizes cells to oxidative stress","volume":"385","author":"Barry","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Cheng, X., Peuckert, C., and W\u00f6lfl, S. (2017). Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-15342-4"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"25856","DOI":"10.1074\/jbc.M102132200","article-title":"Modular Structure of the TIM23 Preprotein Translocase of Mitochondria","volume":"276","author":"Milisav","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.redox.2017.07.005","article-title":"Redox regulation of proteasome function","volume":"13","author":"Lefaki","year":"2017","journal-title":"Redox Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"108059","DOI":"10.1016\/j.celrep.2020.108059","article-title":"Mitochondrial Regulation of the 26S Proteasome","volume":"32","author":"Meul","year":"2020","journal-title":"Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.cell.2017.04.023","article-title":"The Logic of the 26S Proteasome","volume":"169","author":"Collins","year":"2017","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Kumar Deshmukh, F., Yaffe, D., Olshina, M.A., Ben-Nissan, G., and Sharon, M. (2019). The Contribution of the 20S Proteasome to Proteostasis. Biomolecules, 9.","DOI":"10.3390\/biom9050190"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.mam.2016.05.001","article-title":"Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways","volume":"50","author":"Raynes","year":"2016","journal-title":"Mol. Asp. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1042\/bj3350637","article-title":"Comparative resistance of the 20S and 26S proteasome to oxidative stress","volume":"335","author":"Reinheckel","year":"1998","journal-title":"Biochem. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"19458","DOI":"10.3390\/ijms160819458","article-title":"Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?","volume":"16","author":"Ross","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"E763","DOI":"10.1210\/jc.2010-2642","article-title":"Proteasome inhibition induces a p38 MAPK pathway-dependent antiapoptotic program via Nrf2 in thyroid cancer cells","volume":"96","author":"Du","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"648","DOI":"10.2174\/1389200217666160322143631","article-title":"The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity","volume":"17","author":"Cardellach","year":"2016","journal-title":"Curr. Drug Metab."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.trechm.2019.04.009","article-title":"Challenges and Opportunities in Central Nervous System Drug Discovery","volume":"1","author":"Danon","year":"2019","journal-title":"Trends Chem."},{"key":"ref_78","first-page":"1","article-title":"Psychoactive drugs and metabolic disorders","volume":"13","author":"Bezerra","year":"2023","journal-title":"Debates Psiquiatr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.pcl.2016.08.011","article-title":"Presentation and Diagnostic Evaluation of Mitochondrial Disease","volume":"64","author":"Dimmock","year":"2017","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Tang, X., Wang, Z., Hu, S., and Zhou, B. (2022). Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071313"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1093\/icb\/icy017","article-title":"Mitochondrial Adaptations to Variable Environments and Their Role in Animals\u2019 Stress Tolerance","volume":"58","author":"Sokolova","year":"2018","journal-title":"Integr. Comp. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.4049\/jimmunol.1301974","article-title":"Inflammasome Priming by Lipopolysaccharide Is Dependent upon ERK Signaling and Proteasome Function","volume":"192","author":"Ghonime","year":"2014","journal-title":"J. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Cirit, M., Grant, K.G., and Haugh, J.M. (2012). Systemic Perturbation of the ERK Signaling Pathway by the Proteasome Inhibitor, MG132. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050975"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"eaau1330","DOI":"10.1126\/science.aau1330","article-title":"Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes","volume":"364","author":"Sandstrom","year":"2019","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/1873-3468.13327","article-title":"Acetylation modulates LC3 stability and cargo recognition","volume":"593","author":"Song","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.bbabio.2017.09.005","article-title":"Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio","volume":"1858","author":"Anderson","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.molcel.2014.12.013","article-title":"Deacetylation of nuclear LC3 drives autophagy initiation under starvation","volume":"57","author":"Huang","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ymeth.2010.02.003","article-title":"Bias in the Cq value observed with hydrolysis probe based quantitative PCR can be corrected with the estimated PCR efficiency value","volume":"50","author":"Tuomi","year":"2010","journal-title":"Methods"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/gkp045","article-title":"Amplification efficiency: Linking baseline and bias in the analysis of quantitative PCR data","volume":"37","author":"Ruijter","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/S0304-3940(02)01423-4","article-title":"Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data","volume":"339","author":"Ramakers","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e12358","DOI":"10.7717\/peerj.12358","article-title":"Differential p16 expression levels in the liver, hepatocytes and hepatocellular cell lines","volume":"9","author":"Kramar","year":"2021","journal-title":"PeerJ"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.freeradbiomed.2009.12.010","article-title":"Chromatin repair after oxidative stress: Role of PARP-mediated proteasome activation","volume":"48","author":"Catalgol","year":"2010","journal-title":"Free Radic. Biol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:14:36Z","timestamp":1760112876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,16]]},"references-count":92,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011119"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011119","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,16]]}}}