{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:00:35Z","timestamp":1790830835515,"version":"4.1.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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>Introduction<\/jats:title>\n                    <jats:p>Depression is a common mental disorder driven by biopsychosocial factors. Although traditional antidepressants serve as first-line therapies, they face clinical challenges, underscoring the need for novel therapeutic agents with improved efficacy. Our previous studies have identified hippocampal SIK2 as a key regulator in the pathogenesis of depression, acting through the cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1)-CREB-brain derived neurotrophic factor (BDNF) signaling pathway. In this study, we investigated the antidepressant-like effects of GLPG3970, a novel selective inhibitor of SIK2\/3, in male C57BL\/6J mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression were employed, combined with behavioral tests, virus-mediated gene transfer, Western blotting, co-immunoprecipitation, and immunofluorescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>It was found that repeated administration of GLPG3970 significantly suppressed depressive-like behaviors in both CSDS and CUMS model mice, blocked stress-induced increases in hippocampal SIK2 expression and CRTC1 cytoplasmic translocation, and consequently restored the hippocampal BDNF signaling cascade and neurogenesis. More importantly, by using adeno-associated virus (AAV)-mediated overexpression of SIK2 or silencing of CRTC1\/CREB\/BDNF in the hippocampus, the antidepressant-like effects of GLPG3970 in mice were notably eliminated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these findings together demonstrate that the antidepressant-like actions of GLPG3970 in mice depend on the hippocampal SIK2-CRTC1-CREB-BDNF signaling pathway, highlighting its potential as a novel candidate for antidepressant therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1895911","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:50:17Z","timestamp":1790830217000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The selective SIK2\/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models"],"prefix":"10.3389","volume":"17","author":[{"given":"Jia-Yi","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-Yang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Jie","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]},{"name":"Office of Research and Innovation, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]},{"name":"Office of Research and Innovation, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Jing","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Fan","sequence":"additional","affiliation":[{"name":"Office of Research and Innovation, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e18368","DOI":"10.1111\/jcmm.18368","article-title":"BDNF\/TrkB activators in Parkinson's disease: a new therapeutic strategy","volume":"28","author":"Ali","year":"2024","journal-title":"J. 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