Aquaporin 9 drives macrophage M1 polarization and intervertebral disc degeneration by stabilizing p65 to activate NF-κB signaling
Abstract
IntroductionIntervertebral disc degeneration (IVDD) is a primary cause of low back pain, but its molecular mechanisms remain poorly understood, limiting therapeutic development. This study investigates the role of aquaporin 9 (AQP9) in IVDD and its regulation of macrophage M1 polarization through the NF-κB pathway.MethodsAQP9 expression was examined in degenerated nucleus pulposus (NP) tissues from both rodent models and human clinical samples. The functional role of AQP9 was assessed using AAV-mediated AQP9 overexpression and pharmacological inhibition of AQP9. The involvement of the NF-κB pathway was evaluated using an NF-κB specific inhibitor, with M1/M2 macrophage polarization analyzed in vivo and in vitro.ResultsAQP9 expression was significantly upregulated in degenerated NP tissues from both rodent models and human clinical samples. Functionally, AAV-mediated AQP9 overexpression exacerbated IVDD and extracellular matrix (ECM) degradation, while pharmacological inhibition of AQP9 exerted protective effects. Mechanistically, AQP9 directly bound to p65, inhibiting its ubiquitin-proteasome degradation and thereby prolonging p65 protein half-life and enhancing its stability. This sustained p65 activation continuously stimulated the NF-κB pathway, driving macrophage polarization toward a pro-inflammatory M1 phenotype, as evidenced by increased M1 markers and an elevated M1/M2 ratio in vivo and in vitro. The pro-inflammatory and catabolic effects of AQP9 were completely abrogated by an NF-κB specific inhibitor, confirming pathway dependence.DiscussionOur findings elucidate a non-canonical function of AQP9 as a p65 stabilizer, establishing a novel “AQP9-p65-macrophage plasticity” axis that drives IVDD. This work positions AQP9 as a promising diagnostic biomarker and therapeutic target for IVDD, and suggests its potential relevance in other inflammatory degenerative diseases.
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BibTeX
@article{tu2026aquaporin,
title = {{Aquaporin 9 drives macrophage M1 polarization and intervertebral disc degeneration by stabilizing p65 to activate NF-κB signaling}},
author = {Kewu Tu and Tao Zhu and Jinming Xu and Kun Zhao and Dongteng Liao and Zhaomou Chen and Yunhua Luo and Weijie Lai and Jinrong Liang and Chaolong Lu and Ying Yang and Zhengbo Hu and Qiang Wu and Xiangheng Dai},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1954935},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954935},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Aquaporin 9 drives macrophage M1 polarization and intervertebral disc degeneration by stabilizing p65 to activate NF-κB signaling
AU - Kewu Tu
AU - Tao Zhu
AU - Jinming Xu
AU - Kun Zhao
AU - Dongteng Liao
AU - Zhaomou Chen
AU - Yunhua Luo
AU - Weijie Lai
AU - Jinrong Liang
AU - Chaolong Lu
AU - Ying Yang
AU - Zhengbo Hu
AU - Qiang Wu
AU - Xiangheng Dai
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1954935
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954935
AB - IntroductionIntervertebral disc degeneration (IVDD) is a primary cause of low back pain, but its molecular mechanisms remain poorly understood, limiting therapeutic development. This study investigates the role of aquaporin 9 (AQP9) in IVDD and its regulation of macrophage M1 polarization through the NF-κB pathway.MethodsAQP9 expression was examined in degenerated nucleus pulposus (NP) tissues from both rodent models and human clinical samples. The functional role of AQP9 was assessed using AAV-mediated AQP9 overexpression and pharmacological inhibition of AQP9. The involvement of the NF-κB pathway was evaluated using an NF-κB specific inhibitor, with M1/M2 macrophage polarization analyzed in vivo and in vitro.ResultsAQP9 expression was significantly upregulated in degenerated NP tissues from both rodent models and human clinical samples. Functionally, AAV-mediated AQP9 overexpression exacerbated IVDD and extracellular matrix (ECM) degradation, while pharmacological inhibition of AQP9 exerted protective effects. Mechanistically, AQP9 directly bound to p65, inhibiting its ubiquitin-proteasome degradation and thereby prolonging p65 protein half-life and enhancing its stability. This sustained p65 activation continuously stimulated the NF-κB pathway, driving macrophage polarization toward a pro-inflammatory M1 phenotype, as evidenced by increased M1 markers and an elevated M1/M2 ratio in vivo and in vitro. The pro-inflammatory and catabolic effects of AQP9 were completely abrogated by an NF-κB specific inhibitor, confirming pathway dependence.DiscussionOur findings elucidate a non-canonical function of AQP9 as a p65 stabilizer, establishing a novel “AQP9-p65-macrophage plasticity” axis that drives IVDD. This work positions AQP9 as a promising diagnostic biomarker and therapeutic target for IVDD, and suggests its potential relevance in other inflammatory degenerative diseases.
SN - 1664-3224
ER -