Rhapontigenin attenuates neurodegeneration in a parkinson’s disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy

Sep 6, 2025Cellular and molecular life sciences : CMLS

Rhapontigenin reduces brain cell damage in Parkinson’s disease by lowering inflammation through improved microglial removal of damaged mitochondria

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Abstract

Rhapontigenin (Rhap) administration significantly ameliorated motor deficits and neuroinflammation in MPTP-induced Parkinson's disease mice.

Rhap reduced dopaminergic neuron loss and neuroinflammation in a mouse model of Parkinson's disease.
The anti-inflammatory effects of Rhap are associated with the inhibition of the cGAS-STING-NF-κB signaling pathway.
Rhap enhances microglial by binding to PINK1, promoting mitochondrial fission and clearance of damaged organelles.
This activation of mitophagy prevents the leakage of mitochondrial DNA, which is linked to neuroinflammation.
PINK1 deficiency in microglia eliminated Rhap's ability to suppress neuroinflammation and enhance mitophagy.

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Microglial activation-induced neuroinflammation and impaired neuronal are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.

Key numbers

3×

Increase in cytosolic mtDNA

Cytosolic mtDNA levels increased nearly 3 times with MPP exposure.

50 mg/kg or 100 mg/kg

dosage in mice

Mice received at doses of 50 mg/kg or 100 mg/kg.

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Rhapontigenin attenuates neurodegeneration in a parkinson’s disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy

Abstract

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