{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:41:38Z","timestamp":1785436898373,"version":"3.56.0"},"reference-count":81,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","award":["202006300052"],"award-info":[{"award-number":["202006300052"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","award":["202206300004"],"award-info":[{"award-number":["202206300004"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]},{"award":["202006300052"],"award-info":[{"award-number":["202006300052"]}],"id":[{"id":"https:\/\/ror.org\/04atp4p48","id-type":"ROR","asserted-by":"publisher"}]},{"award":["202206300004"],"award-info":[{"award-number":["202206300004"]}],"id":[{"id":"https:\/\/ror.org\/04atp4p48","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Consejo Nacional de Humanidades, Cienciasy Tecnolog\u00edas (CONAHCYT) Scholarship","award":["2021-000022-01EXTF-00086"],"award-info":[{"award-number":["2021-000022-01EXTF-00086"]}]},{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"crossref","award":["WE.03-2018-04"],"award-info":[{"award-number":["WE.03-2018-04"]}],"id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"crossref","award":["WE.03-2019-05"],"award-info":[{"award-number":["WE.03-2019-05"]}],"id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"crossref"}]},{"award":["WE.03-2018-04"],"award-info":[{"award-number":["WE.03-2018-04"]}],"id":[{"id":"https:\/\/ror.org\/03cw2h814","id-type":"ROR","asserted-by":"publisher"}]},{"award":["WE.03-2019-05"],"award-info":[{"award-number":["WE.03-2019-05"]}],"id":[{"id":"https:\/\/ror.org\/03cw2h814","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Parkinson Fonds"},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["IRTG1874DIAMICOM-SP2"],"award-info":[{"award-number":["IRTG1874DIAMICOM-SP2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"award":["IRTG1874DIAMICOM-SP2"],"award-info":[{"award-number":["IRTG1874DIAMICOM-SP2"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Novartis","award":["50199468"],"award-info":[{"award-number":["50199468"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Air pollution is a growing hazard to global health. Epidemiological studies have reported a potential role of air pollutant exposure in the development or aggravation of neurodegenerative diseases. However, the underlying mechanisms are ill-defined. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of cell death that drives neuronal loss in neurodegenerative diseases. Our previous studies reported the involvement of adenosine 3\u2032,5\u2032-cyclic monophosphate (cAMP) and EPAC (exchange protein directly activated by cAMP) in ferroptotic cell death. Here, we investigated the effects of diesel exhaust particles (DEP) in mouse hippocampal (HT22) neuronal cells. Our data showed that toxicity induced by RSL3 (50\u201375 nM), a ferroptosis inducer, was significantly increased by the addition of DEP (100 \u03bcg\/mL). Pharmacological inhibition of EPAC1 (CE3F4 30 \u03bcM or AM-001 30 \u03bcM) and soluble adenylyl cyclase (sAC; TDI-10229 1 \u03bcM or TDI-11861 0.1 \u03bcM) prevented enhanced ferroptotic HT22 cell death caused by DEP, while pharmacological modulation of EPAC2, protein kinase A (PKA), phosphodiesterases (PDEs), or transmembrane AC did not. DEP in combination with RSL3 exposure increased intracellular calcium levels and induced lysosomal de-acidification. Furthermore, inhibition of EPAC1 prevented mitochondrial ROS (MitoSOX) and lipid peroxidation (BODIPY C11 and MDA levels) after DEP and RSL3 co-exposure. Collectively, EPAC1 may serve as a novel target for the treatment or prevention of neurodegenerative diseases accelerated by air pollution.<\/jats:p>","DOI":"10.3390\/antiox15050566","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:03:47Z","timestamp":1777536227000},"page":"566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of EPAC1 Prevents Neuronal Death Mediated by Diesel Exhaust Particles in Ferroptotic Cell Death Conditions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3276-7201","authenticated-orcid":false,"given":"Hong","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leshan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana L.","family":"Manzano-Covarrubias","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Groningen Research Institute of Asthma and COPD (GRIAC), University Medical Center Groningen (UMCG), University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoeja S.","family":"Gadjdjoe","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Land","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina H. J. T.","family":"M. van der Veen","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8780-4252","authenticated-orcid":false,"given":"Teresa","family":"Mitchell-Garcia","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1976-736X","authenticated-orcid":false,"given":"Heba A.","family":"Fayyaz","sequence":"additional","affiliation":[{"name":"Department of Nanomedicine and Drug Targeting, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Venema","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6886-7239","authenticated-orcid":false,"given":"Christoffer","family":"\u00c5berg","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0859-8572","authenticated-orcid":false,"given":"Marieke","family":"van der Hart","sequence":"additional","affiliation":[{"name":"Analytical Biochemistry, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Quantall B.V., L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5239-6017","authenticated-orcid":false,"given":"Frank","family":"Lezoualc\u2019h","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Toulouse, Inserm, Institut des Maladies M\u00e9taboliques et Cardiovasculaires, I2MC, 31432 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-1694","authenticated-orcid":false,"given":"Xiaodong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology & Pharmacology, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX 7000, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-5614","authenticated-orcid":false,"given":"Amalia M.","family":"Dolga","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3075-0630","authenticated-orcid":false,"given":"Martina","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Groningen Research Institute of Asthma and COPD (GRIAC), University Medical Center Groningen (UMCG), University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, September 22). 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