{
  "abstract": "Introduction: 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.\n\nMethods: 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.\n\nResults: 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.\n\nDiscussion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology, School of Pharmacy, Nantong University , , ,",
    "Office of Research and Innovation, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jia-Yi Shen"
    },
    {
      "affs": [
        0
      ],
      "name": "Lu Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Fei-Yang Jin"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun-Jie Qian"
    },
    {
      "affs": [
        0
      ],
      "name": "Feng Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Ruo-Jia Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Meng-Jing Qi"
    },
    {
      "affs": [
        0
      ],
      "name": "Bo Jiang"
    },
    {
      "affs": [
        1
      ],
      "name": "Hua Fan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bczzc4s50adg0.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1895911",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668743/?tool=EBI",
  "id": "bczzc4s50adg0",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13668743",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2736|Treatment of Major Depression"
    ]
  ],
  "openalex": "W7215059801",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668743/pdf/?tool=EBI",
  "pmcid": "PMC13668743",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/bczzc4s50adg0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:18Z",
      "native_id": "PMC:PMC13668743",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13668743"
    },
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1895911",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1895911/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Treatment of Major Depression",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models",
  "title_text": "The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:06Z",
  "url": "https://research.draconitic.com/paper/bczzc4s50adg0",
  "venue": "Frontiers in pharmacology",
  "versions": []
}