Autophagy in neuropathic pain: Cell specificity, molecular mechanisms, and therapeutic prospects

Abstract

Neuropathic pain (NP) is a chronic pain caused by damage or disease of the somatosensory system, with a global prevalence of 6.9%–10%. Due to the limited efficacy of current clinical treatments, there is an urgent need to explore new therapeutic targets. Autophagy, a highly conserved catabolic process in eukaryotic cells, maintains intracellular homeostasis by clearing damaged proteins and organelles. Recent studies indicate that autophagy plays a complex and bidirectional role in the development of NP, participating in the pain process by modulating the functional states of neurons, microglia, and astrocytes. This review systematically elaborates on the cell-specific roles of autophagy in NP, its dual regulatory mechanisms (protective vs. potentially detrimental), the associated molecular networks, and therapeutic strategies. By integrating pathways involving upstream energy and stress sensors (AMPK, SIRT1, mTOR), transcriptional/epigenetic regulators (Nrf2, miRNAs), and inflammation/immune hubs (TLR, NLRP3 inflammasome), we construct a comprehensive regulatory network of autophagy in NP. Finally, the article critically assesses the translational potential of autophagy-targeting strategies and provides an outlook on future research directions, offering a theoretical basis for developing novel NP treatments through autophagy modulation.