{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T14:13:31Z","timestamp":1785507211068,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973007"],"award-info":[{"award-number":["81973007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81973007"],"award-info":[{"award-number":["81973007"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Excessive manganese (Mn) exposure is associated with neuroinflammation and cognitive impairment, yet the contribution of endogenous pro-resolving pathways to Mn neurotoxicity remains incompletely understood. Here, we examined the involvement of the lipocalin-type prostaglandin D synthase (L-PGDS)\/15-deoxy-\u039412,14-prostaglandin J2 (15d-PGJ2) pathway using Mn-treated male C57BL\/6J mice, BV2 microglia, and SH-SY5Y neurons, together with data from occupationally Mn-exposed workers (cross-sectional, hypothesis-generating). In the occupational cohort, circulating 15d-PGJ2 levels and L-PGDS expression were reduced following Mn exposure, consistent with the experimental findings. PPI network analysis and promoter prediction highlighted C\/EBP\u03b2 and MMP9 as potential mediators of Mn-induced neuroinflammatory responses. Consistent with these observations, Mn exposure increased C\/EBP\u03b2 and MMP9 expression, promoted M1 microglial polarization, elevated ROS production, and aggravated neuronal injury in a microglia\u2013neuron co-culture system. Knocking down either C\/EBP\u03b2 or MMP9 attenuated inflammatory activation and oxidative stress and reduced neuronal damage. Administration of exogenous 15d-PGJ2 suppressed Mn-induced increases in C\/EBP\u03b2 and MMP9, alleviated inflammatory and oxidative responses, and partially ameliorated cognitive impairment in Mn-exposed mice. Transcriptomic analyses further showed that 15d-PGJ2 counteracted a substantial proportion of Mn-induced transcriptional alterations, particularly those related to inflammatory and neurodevelopmental processes. In addition, Ptgds knockdown reduced endogenous 15d-PGJ2 production and increased MMP9 expression, whereas exogenous 15d-PGJ2 largely reversed these changes. Together, these findings support the involvement of L-PGDS\/15d-PGJ2 pathway dysregulation in Mn-induced neuroinflammation and suggest that restoration of 15d-PGJ2 signaling may represent a potential therapeutic approach for Mn-associated neurotoxicity.<\/jats:p>","DOI":"10.3390\/antiox15080957","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T13:23:20Z","timestamp":1785504200000},"page":"957","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Downregulation of the L-PGDS\/15d-PGJ2 Pathway Is Associated with Manganese-Induced Neuroinflammation and Cognitive Impairment Involving C\/EBP\u03b2 and MMP9"],"prefix":"10.3390","volume":"15","author":[{"given":"Junrou","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2038-7156","authenticated-orcid":false,"given":"Kai","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Occupational Health, Beijing Center for Disease Control and Prevention, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0155-3438","authenticated-orcid":false,"given":"Piye","family":"Niu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environment and Aging, School of Public Health, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1017\/qpb.2025.10012","article-title":"Manganese handling in plants: Advances in the mechanistic and functional understanding of transport pathways","volume":"6","author":"Meier","year":"2025","journal-title":"Quant. 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