In MPTP-treated mice and astrocyte cultures, inhibition of S100A9 with paquinimod reversed senescence markers, reduced SASP factors, restored mitochondrial biogenesis gene expression and TH-positive fibers, and improved motor behavior, while recombinant S100A9 induced senescence-like and…

Provides a druggable link between aging-related cellular senescence, mitochondrial dysfunction, and dopaminergic neurodegeneration in PD, highlighting paquinimod repurposing potential and a clear target for follow-up translational studies.

Aging is the most important risk factor for Parkinson's disease (PD). S100A9, a calcium-binding protein, is closely related to a variety of aging-related diseases, but its role in the pathogenesis of PD is still unclear. This study aims to investigate the role of S100A9 in aging-related mechanisms in PD. C57BL/6J mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP; 15 mg/kg four times daily), followed by Paquinimod (a S100A9 inhibitor; 7 mg/kg, once a day for 7 days after model establishment, totaling 8 doses). We found that MPTP induced significant motor deficits and dopaminergic nerve damage, accompanied by up-regulation of p21 expression, down-regulation of Lamin B1 expression, and significant increases in SASP factors such as MMP9, IL-1α, IL-1β, and IL-6. Treatment with recombinant S100A9 protein induced senescence-like molecular alterations and reduced expression of mitochondrial biogenesis-associated genes in astrocytes in vitro. Inhibition of S100A9 effectively improved movement disorders, restore TH-positive fiber density, reduce the expression of cell senescence markers and SASP factors, and up-regulate mitochondrial function-related genes. Studies have shown that S100A9 plays a key bridge between aging and neurodegeneration in PD. Inhibition of S100A9 may be a potential therapeutic strategy to alleviate cell senescence and mitochondrial damage in PD.