{
  "abstract": "The biological role of hydrogen persulfide (H₂S₂) has remained elusive due to the scarcity of controllable donors, despite its importance as a reactive sulfur species whose dyshomeostasis drives neuroinflammation. Herein, we employed HPD1, a novel esterase-responsive H₂S₂ donor, to investigate its anti-inflammatory effects and underlying mechanisms in lipopolysaccharide (LPS)-stimulated glial cells. HPD1 exhibited superior cytoprotective and anti-inflammatory efficacy over inorganic sodium disulfide (Na₂S₂) and sodium hydrosulfide (NaHS) in BV2 microglia, consistent with its superior and sustained intracellular H₂S₂ release efficiency. Functionally, HPD1 dose-dependently attenuated LPS-induced cytotoxicity and shifted microglia and primary astrocytes from pro-inflammatory, neurotoxic states toward anti-inflammatory, neuroprotective phenotypes, as characterized by M1-to-M2 and A1-to-A2 marker profiles, respectively. Mechanistically, HPD1 downregulated toll-like receptor 4 (TLR4) and attenuated mitogen-activated protein kinase (MAPK) activation, as evidenced by reduced extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK) phosphorylation in BV2 microglia. In both BV2 microglia and primary astrocytes, HPD1 markedly suppressed the phosphorylation of both the p65 subunit of nuclear factor-κB (NF-κB) and inhibitor of κBα (IκBα), prevented the proteasomal degradation of IκBα, and blocked the nuclear translocation of p65. Consequently, HPD1 attenuated the release of neuroinflammatory mediators while promoting the production of neuroprotective factors, thereby protecting neuronal HT22 cells against neurotoxicity induced by conditioned medium from LPS-activated BV2 microglia. In vivo, HPD1 reduced serum proinflammatory cytokine levels in both an acute intrathecal LPS-induced neuroinflammation model and a chronic constriction injury-induced neuropathic pain model. Collectively, our findings identify the TLR4-MAPK/NF-κB axis as a potential molecular pathway through which sustained H₂S₂ delivery by HPD1 reprograms glial phenotypic polarization and promotes neuroprotection. This study provides mechanistic insights into H₂S₂ signaling and supports the therapeutic potential of controllable H₂S₂ supplementation for neuroinflammatory disorders.",
  "abstract_shown": true,
  "affiliations": [
    "Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.",
    "Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.",
    "Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China. Electronic address: 997060@hainanu.edu.cn.",
    "Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: fengping@wchscu.cn.",
    "Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: bowenke@scu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Fei Yan"
    },
    {
      "affs": [
        1
      ],
      "name": "Shouwei Tao"
    },
    {
      "affs": [
        1
      ],
      "name": "Yan Jiao"
    },
    {
      "affs": [
        1
      ],
      "name": "Ting Kang"
    },
    {
      "affs": [
        0
      ],
      "name": "Shuangqing Du"
    },
    {
      "affs": [
        0
      ],
      "name": "Yue Cheng"
    },
    {
      "affs": [
        2
      ],
      "name": "Zhenbo Huang"
    },
    {
      "affs": [
        3
      ],
      "name": "Ping Feng"
    },
    {
      "affs": [
        4
      ],
      "name": "Bowen Ke"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1a6y4wvx5mxs2.bib",
  "cited_by": 0,
  "doi": "10.1016/j.redox.2026.104430",
  "fulltext_url": "https://europepmc.org/articles/PMC13693069",
  "id": "1a6y4wvx5mxs2",
  "issns": [
    "2213-2317"
  ],
  "landing_url": "https://europepmc.org/article/MED/42880019",
  "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",
      "1303|Sulfur Compounds in Biology"
    ]
  ],
  "openalex": "W7220946969",
  "pdf_url": "https://europepmc.org/articles/PMC13693069?pdf=render",
  "pmcid": "PMC13693069",
  "pmid": "42880019",
  "published": "2026-10-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1a6y4wvx5mxs2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:00Z",
      "native_id": "MED:42880019",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42880019"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "journal-openalex:1312|Redox biology and oxidative stress",
      "subfield": "molecular-biology"
    }
  ],
  "title": "A novel hydrogen persulfide donor HPD1 alleviated LPS-induced neuroinflammation by modulating glial polarization through TLR4-MAPK/NF-κB pathway.",
  "title_text": "A novel hydrogen persulfide donor HPD1 alleviated LPS-induced neuroinflammation by modulating glial polarization through TLR4-MAPK/NF-κB pathway.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:00Z",
  "url": "https://research.draconitic.com/paper/1a6y4wvx5mxs2",
  "venue": "Redox biology",
  "versions": []
}