Integrated bioinformatics and experimental validation reveal that kaempferol ameliorates intervertebral disc degeneration via dual anti-inflammatory and anti-aging pathways.

Authors

Dongyang Li, Xiaofei Wu, Feng Chen, Chao Song, Zhiwei Xu

Published in

Naunyn-Schmiedeberg's archives of pharmacology. Jul 29, 2026. Epub Jul 29, 2026.

Abstract

Intervertebral disc degeneration (IVDD) is a degenerative disease characterized by degradation of the extracellular matrix (ECM) in the nucleus pulposus, disruption of the fibrous ring structure, and imbalance of the inflammatory microenvironment. It is the main cause of chronic low back pain. Its pathogenesis is closely related to cellular aging and immune inflammation. Aging nucleus pulposus cells release pro-inflammatory factors such as IL-6 and TNF-α through the secretion of senescence associated secretory phenotype (SASP), recruiting M1 macrophages to infiltrate and forming a vicious cycle of "aging inflammation matrix destruction." This study systematically analyzed the molecular mechanism by which kaempferol improves IVDD through multi-target regulation by integrating bioinformatics analysis, animal experiments, and cell models. Bioinformatics screening revealed significant abnormal expression of genes such as AURKB, CCNB1, AXL, NEK6, and PTK2 in IVDD degenerated tissues. Downregulation of CCNB1 induced G2/M phase arrest by inhibiting CDK1 activity, while activation of GSK3B inhibited the Wnt signaling pathway by phosphorylating β-catenin, exacerbating ECM catabolism. Proteomics further confirms that the NOX4 mediated ROS-p38 MAPK pathway promotes cell apoptosis and SASP secretion. Immune infiltration analysis showed that M1 macrophages were significantly enriched in degenerated intervertebral discs, and their secreted IL-6 and TNF-α amplified the inflammatory cascade by activating the NF-κ B pathway. Animal experiments have shown that intervention with kaempferol can partially restore the intervertebral disc height index (DHI), downregulate the levels of IL‑1β and TNF‑α, upregulate the expression of CCNB1 and AURKB (which were downregulated in the IVDD model), thereby alleviating G2/M phase arrest and promoting cell cycle progression, inhibit AXL and PTK2, and reduce macrophage infiltration. Mechanistically, kaempferol inhibits NOX4 activity by clearing ROS, blocking the vicious cycle of oxidative stress‑inflammation; by regulating the NEK6/NF‑κB axis, the expression of MMP‑3 and ADAMTS‑4 is reduced, delaying ECM degradation; and improve the immune microenvironment by promoting macrophage polarization towards the M2 phenotype. In addition, kaempferol can reverse the metabolic imbalance mediated by GSK3B. This study reveals for the first time that kaempferol upregulates core gene networks such as AURKB and CCNB1 while suppressing AXL through the "anti‑inflammatory anti‑aging" dual pathway, thereby breaking the "aging‑immunity" crosstalk and restoring cell cycle homeostasis, providing a new strategy for natural compound intervention in IVDD treatment.

PMID:
42525295
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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