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Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)

  • Authors:
    • Xilong Guan
    • Linan Zha
    • Xiaoling Zhu
    • Xiuqin Rao
    • Xiangfei Huang
    • Yanhong Xiong
    • Youwei Guo
    • Mojiao Zhang
    • Dongshan Zhou
    • Qikun Tu
    • Jianhang Wu
    • Xifeng Wang
    • Fuzhou Hua
    • Jing Xu
  • View Affiliations / Copyright

    Affiliations: Department of Anesthesiology, Yingtan City People's Hospital, Yingtan, Jiangxi 335099, P.R. China, Key Laboratory of Anesthesiology of Jiangxi, Nanchang, Jiangxi 330006, P.R. China
    Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 147
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    Published online on: July 16, 2025
       https://doi.org/10.3892/ijmm.2025.5588
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Abstract

The complex of proteins S100A8/A9 has been recognized as a major initiator of cognitive disorder onset, including, but not restricted to, neuroinflammation. Cognitive impairment or decline in memory, attention and executive function has been on the rise and is a major public health priority. Several neurological conditions that affect the brain and cognitive processes, including central nervous system diseases such as Alzheimer's disease and stroke, and systemic diseases, such as sepsis and systemic lupus erythematosus, are associated with S100A8/A9. Experiments have progressively demonstrated that S100A8/A9 plays a role in cognitive decline, as it regulates cognitive domains, including sleep, learning, memory, and emotion control, via several mechanisms. In this review, a critical overview of the role of S100A8/A9 in the treatment of neurocognitive diseases is provided, including the regulation of brain function and the pathogenesis of diseases, and potential novel therapies are suggested. It is necessary to study S100A8/A9 alone as an alternative marker for the diagnosis and treatment of neurocognitive diseases, and in line with the requirements of therapy for cognitive impairment. As S100A8/A9 research continues, the understanding and treatment of neurocognitive diseases may improve.
View Figures

Figure 1

Diagram of p38-MAPK activation and
the regulatory mechanism of neuroinflammation. First, S100A8/A9
binds to theTLR4 receptor and activates the upstream kinases MKK3
and MKK6. These kinases can phosphorylate Thr180 and Tyr182 in the
p38 MAPK activation loop. This causes double phosphorylation and
stabilizing the activation loop in an open conformation, thus
activating p38-MAPK. Next, activated p38-MAPK is able to regulate
the inflammatory response by phosphorylating a series of
substrates, such as HSP27, ATF-2 and LPS-1. These processes play a
key role in the pathophysiology of neuroinflammation. The
relationship between activation and regulation is indicated by
arrows in the figure, and the distinction of lines and colors
clearly shows the interactions between molecules and the direction
of signaling. TLR4, Toll-like receptor 4; MKK3, mitogen-activated
protein kinase kinase 3; p38-MAPK, p38-mitogen-activated protein
kinase; Hsp27, heat shock protein 27; ATF-2, activating
transcription factor 2; LSP-1, lymphocyte-specific protein 1.

Figure 2

Schematic illustration of
S100A8/A9-mediated neuroinflammatory signaling pathways. The role
of S100A8/A9 in neuroinflammation and its contribution to
neurodegenerative changes and synaptic dysfunction are outlined. In
the hippocampal neurons, S100A8/A9 interacts with RAGE and TLR4
receptors, triggering intracellular signaling cascades. The
activation of the NF-κB pathway involves the phosphorylation and
degradation of IκB, allowing NF-κB to translocate into the nucleus
and initiate the transcription of pro-inflammatory genes.
Simultaneously, the MAPK pathway is activated via TLR4, leading to
the phosphorylation of p38-MAPK. These pathways collectively result
in the release of inflammatory mediators such as TNF-α and IL-6,
which exacerbate neuroinflammation. The figure also highlights the
cellular environment where these processes occur, emphasizing the
inflammatory microenvironment that supports the progression of
neurodegenerative changes and synaptic dysfunction. RAGE, receptor
for advanced glycation end products; TLR4, Toll-like receptor 4;
NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells;
IκB, inhibitor of κB; MAPK, mitogen-activated protein kinase;
p38-MAPK, p38 mitogen-activated protein kinase; TNF-α, tumor
necrosis factor α; IL-6, interleukin 6.

Figure 3

Mechanistic role of S100A8/A9 in AD
pathology within the hippocampus. S100A8/A9 interacts with RAGE and
TLR4 receptors on neuronal cells, leading to the activation of
intracellular signaling pathways such as NF-κB and MAPK. The
activation of these pathways results in the release of inflammatory
mediators like TNF-α and IL-6. Additionally, S100A8/A9 influences
Aβ production by interacting with APP processing and β-secretase.
The co-location of S100A8/A9 with Aβ plaques and its impact on
neurodegenerative changes and synaptic dysfunction in the
hippocampus are also highlighted. AD, Alzheimer's disease; RAGE,
receptor for advanced glycation end products; TLR4, Toll-like
receptor 4; NF-κB, nuclear factor κ-light-chain-enhancer of
activated B cells; MAPK, mitogen-activated protein kinase; TNF-α,
tumor necrosis factor α; IL-6, interleukin 6; Aβ, amyloid-β; APP,
amyloid precursor protein; HSA, human serum albumin.

Figure 4

S100A8/A9-induced neuroinflammatory
pathways in stroke. This figure illustrates the inflammatory
processes in stroke, highlighting the role of S100A8/A9 in
microglial activation and inflammation. In the brain tissue
affected by stroke, S100A8/A9 interacts with TLR4 on general
microglial cells and BV-2 microglial cells. This interaction
activates the NF-B pathway, leading to the degradation of IκB and
the subsequent release of pro-inflammatory cytokines such as TNF-α
and IL-6. Additionally, the MAPK pathway is activated via TLR4 and
RAGE, further contributing to inflammation. The figure also
emphasizes the injury to oligodendrocyte precursor cells and the
overall inflammatory microenvironment that exacerbates tissue
damage post-stroke. TLR4, Toll-like receptor 4; NF-κB, nuclear
factor κ-light-chain-enhancer of activated B cells; IκB, inhibitor
of κB; MAPK, mitogen-activated protein kinase; TNF-α, tumor
necrosis factor α; IL-6, interleukin 6; RAGE, receptor for advanced
glycation end products; LPS, lipopolysaccharides.
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Copy and paste a formatted citation
Spandidos Publications style
Guan X, Zha L, Zhu X, Rao X, Huang X, Xiong Y, Guo Y, Zhang M, Zhou D, Tu Q, Tu Q, et al: Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review). Int J Mol Med 56: 147, 2025.
APA
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y. ... Xu, J. (2025). Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review). International Journal of Molecular Medicine, 56, 147. https://doi.org/10.3892/ijmm.2025.5588
MLA
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., Wu, J., Wang, X., Hua, F., Xu, J."Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)". International Journal of Molecular Medicine 56.4 (2025): 147.
Chicago
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., Wu, J., Wang, X., Hua, F., Xu, J."Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 147. https://doi.org/10.3892/ijmm.2025.5588
Copy and paste a formatted citation
x
Spandidos Publications style
Guan X, Zha L, Zhu X, Rao X, Huang X, Xiong Y, Guo Y, Zhang M, Zhou D, Tu Q, Tu Q, et al: Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review). Int J Mol Med 56: 147, 2025.
APA
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y. ... Xu, J. (2025). Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review). International Journal of Molecular Medicine, 56, 147. https://doi.org/10.3892/ijmm.2025.5588
MLA
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., Wu, J., Wang, X., Hua, F., Xu, J."Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)". International Journal of Molecular Medicine 56.4 (2025): 147.
Chicago
Guan, X., Zha, L., Zhu, X., Rao, X., Huang, X., Xiong, Y., Guo, Y., Zhang, M., Zhou, D., Tu, Q., Wu, J., Wang, X., Hua, F., Xu, J."Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 147. https://doi.org/10.3892/ijmm.2025.5588
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