A new review published in Journal of Holistic Integrative Pharmacy reveals that autophagy—the cellular recycling system that clears damaged proteins and organelles — acts as a double-edged sword in neuropathic pain. Depending on the cell type, disease stage and activation intensity, autophagy can either protect against or contribute to chronic pain.
The authors, from the School of Basic Medical Sciences at Guandong Pharmaceutical University, analyzed how autophagy functions differently across three key cell types in the central nervous system: neurons, astrocytes and microglia. They also mapped the molecular network, involving energy sensors (AMPK/SIRT1/mTOR), transcriptional regulators (Nrf2) and immune hubs (TLR pathways and NLRP3 inflammasome), that collectively governs autophagic activity in neuropathic pain.
A main finding is that autophagy impairment in specific brain regions, such as the prelimbic cortex, is linked to anxiety and depression that frequently accompany chronic pain, suggesting that targeting autophagy might address not just pain but its emotional comorbidities.
"Autophagy is not simply all "good" or "bad”," says senior and co-corresponding author Jing Liu. "In neurons, moderate autophagy protects synaptic function, but excessive activation can promote degeneration. In astrocytes and microglia, autophagy determines whether these cells become pro-inflammatory or protective, directly influencing pain outcomes."
The authors also reviewed current therapeutic approaches, from repurposed drugs like metformin and minocycline to natural compounds such as curcumin. "While these agents show promise in preclinical studies, successful clinical translation will require cell-specific targeting, improved drug delivery systems (particularly for crossing the blood-brain barrier) and careful timing of interventions," says Liu.
"Rather than simply activating or inhibiting autophagy globally, future therapies must achieve precision modulation—like a dimmer switch rather than an on-off switch," adds co-author Yagi Yang. "This means developing drugs that target specific cell types or even subcellular compartments and delivering them at the right disease stage."
With neuropathic pain affecting 6.9–10% of the global population and fewer than half of patients responding adequately to current treatments, this framework offers new hope for more effective, personalized pain management strategies.
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Contact the author: Jing Liu, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China. Email: liujing@gdpu.edu.cn
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Journal of Holistic Integrative Pharmacy
Autophagy in neuropathic pain: Cell specificity, molecular mechanisms, and therapeutic prospects
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.