2. Academic Validation
  3. Protocatechuic acid alleviates cGAS-STING-mediated neuroinflammation by enhancing microglial autophagy in mouse models of Parkinson's disease

Protocatechuic acid alleviates cGAS-STING-mediated neuroinflammation by enhancing microglial autophagy in mouse models of Parkinson's disease

  • Phytomedicine. 2025 Nov 25:148:157493. doi: 10.1016/j.phymed.2025.157493.
Wenjuan Rui 1,  Zihan Chen 1,  Shun Tao 1,  Xiaoyan Yao 1,  Wenting Xie 2,  Dengli Qin 1,  Zhihan Ye 1,  Yuqing Wu 3,  Lieying Fan 4,  Sheng Li 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, 200120 Shanghai, China.
  • 2 Department of Neurology, The First Affiliated Hospital, Anhui University of Traditional Chinese Medicine, 230031 Hefei, China.
  • 3 Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China. Electronic address: [email protected].
  • 4 Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, 200120 Shanghai, China. Electronic address: [email protected].
  • 5 Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, 200120 Shanghai, China. Electronic address: [email protected].
PMID: 41218352 DOI: 10.1016/j.phymed.2025.157493
Abstract

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron loss and neuroinflammation. The cGAS-STING pathway-mediated innate immune inflammation has been implicated in PD pathogenesis, but its interplay with Autophagy in PD remains poorly understood. Protocatechuic acid (PCA), a bioactive polyphenol metabolite, exhibits neuroprotective properties; however, its effects on Autophagy and cGAS-STING signaling in PD has not been investigated.

Purpose: This study aimed to elucidate the neuroprotective effects of PCA against PD and its underlying mechanisms in suppressing cGAS-STING-mediated inflammation.

Methods: Using N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and A30P transgenic PD mouse models, we evaluated the neuroprotective effects of PCA through behavioral tests and immunohistochemistry. And we examined the changes in cGAS-STING pathway and related inflammation using qPCR, ELISA, and western blotting. Primary microglia cultures and microglia-specific Atg5 knockout mice were employed to dissect the role of Autophagy in PCA-mediated inhibition of cGAS-STING signaling.

Results: PCA administration alleviated motor deficits, reduced dopaminergic neuron loss, and suppressed neuroinflammation in the PD models. Mechanistically, PCA enhanced Autophagy, promoting the clearance of damaged DNA and inhibiting cGAS-STING pathway activation, as evidenced by the reduced phosphorylation of TBK1, IRF3, and NF-κB. Microglial Atg5 deletion abolished the anti-inflammatory and neuroprotective effects of PCA, confirming its Autophagy dependence. In A30P mice, PCA also attenuated α-synuclein Aggregation and improved motor function.

Conclusion: Our study identifies a novel mechanism linking natural metabolite PCA to the autophagy-cGAS-STING axis in PD. Our findings highlight the critical crosstalk between Autophagy and innate immunity in PD pathogenesis and propose PCA as a promising disease-modifying strategy.

Keywords

Autophagy; Parkinson’s disease; Protocatechuic acid; STING; cGAS.

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