A novel hydrogen persulfide donor HPD1 alleviated LPS-induced neuroinflammation by modulating glial polarization through TLR4-MAPK/NF-κB pathway.
5 affiliations
- 1Clinical 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.
- 2Department 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.
- 3Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China. Electronic address: [email protected].
- 4Clinical 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: [email protected].
- 5Department 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: [email protected].
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.
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BibTeX
@article{yan2026novel,
title = {{A novel hydrogen persulfide donor HPD1 alleviated LPS-induced neuroinflammation by modulating glial polarization through TLR4-MAPK/NF-κB pathway.}},
author = {Fei Yan and Shouwei Tao and Yan Jiao and Ting Kang and Shuangqing Du and Yue Cheng and Zhenbo Huang and Ping Feng and Bowen Ke},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104430},
url = {https://europepmc.org/article/MED/42880019},
note = {CC BY},
}
RIS
TY - JOUR
TI - A novel hydrogen persulfide donor HPD1 alleviated LPS-induced neuroinflammation by modulating glial polarization through TLR4-MAPK/NF-κB pathway.
AU - Fei Yan
AU - Shouwei Tao
AU - Yan Jiao
AU - Ting Kang
AU - Shuangqing Du
AU - Yue Cheng
AU - Zhenbo Huang
AU - Ping Feng
AU - Bowen Ke
PY - 2026
DA - 2026/10/08
JO - Redox biology
DO - 10.1016/j.redox.2026.104430
UR - https://europepmc.org/article/MED/42880019
AB - 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.
SN - 2213-2317
ER -