{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T06:02:51Z","timestamp":1780293771457,"version":"3.54.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Given the substantial clinical and financial burden of Recurrent Depressive Disorder (RDD) and the critical lack of reliable biomarkers, this study investigated plasma exosomal microRNA (miRNA) as candidate biomarkers and therapeutic targets to overcome reliance on subjective diagnosis. The pathogenesis of RDD remains incompletely understood. To this end, we focused on miR-618 and conducted\n                      <jats:italic>in vivo<\/jats:italic>\n                      functional experiments to reveal its molecular mechanism in RDD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Differentially expressed miRNAs (DEmiRNAs) in plasma exosomes between RDD patients and healthy controls (HCs) were identified using high-throughput sequencing and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve analysis was used to evaluate their diagnostic value for RDD. Biological functions and pathways of DEmiRNA target genes were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The miR-618 delivery vector was constructed by utilizing the exosomes secreted by HEK293\u00a0T cells. The molecular functions of miR-618 were verified through\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High-throughput sequencing analysis identified 49 DEmiRNAs between the RDD patients and HCs. Subsequent validation via RT-qPCR demonstrated marked upregulation of miR-618 and miR-223\u20133p expression in plasma exosomes derived from RDD patients relative to HCs. ROC curve analysis indicated that miR-618 and miR-223\u20133p exhibited good diagnostic performance for RDD, with areas under the ROC curve (AUC) of 0.782 and 0.762, respectively. GO and KEGG pathway enrichment analyses indicated significant associations of DEmiRNAs target genes with key biological processes such as ER to Golgi ceramide transport and calcium ion export, and specific pathways including PI3K-Akt signaling pathway, MAPK signaling pathway and Wnt signaling pathway, etc. Functional validation\n                      <jats:italic>in vivo<\/jats:italic>\n                      indicated that miR-618 contributes to depression-like behaviors by regulateing the PI3K-Akt pathway and subsequently inducing neuronal and synaptic plasticity impairment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MiR-618 and miR-223\u20133p in plasma exosomes can serve as candidate non-invasive biomarkers for RDD. miR-618 contributes to depression-like behaviors by regulateing the PI3K-Akt pathway and subsequently inducing neuronal and synaptic plasticity impairment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1816232","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:29:06Z","timestamp":1780291746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification and functional characterization of plasma exosomal miR-618 as a novel biomarker in recurrent depressive disorder"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiangyang","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Jiamusi University","place":["Jiamusi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Psychiatric Center, Xiamen Xianyue Hospital Affiliated with Xiamen Medical College, Xiamen Xianyue Hospital, Fujian Clinical Research Center for Mental Disorders","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meitao","family":"Duan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxian","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University","place":["Jiamusi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Fujian Province University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9265","DOI":"10.1039\/d3fo02222f","article-title":"Unleashing lactoferrin's antidepressant potential through the PI3K\/Akt\/mTOR pathway in chronic restraint stress rats","volume":"14","author":"Ahmed","year":"2023","journal-title":"Food Funct."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4066","DOI":"10.4049\/jimmunol.1200728","article-title":"Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats","volume":"190","author":"Bergman","year":"2013","journal-title":"J. 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