Focusing on inflammation-driven pyroptosis in postherpetic neuralgia: from molecular mechanisms to therapeutic strategies.

Postherpetic neuralgia (PHN), the most frequent and recalcitrant sequela of herpes zoster, arises from a complex interplay between inflammatory cascades and programmed cell death. Emerging evidence indicates that pyroptosis-a form of inflammatory cell death mediated by the NLRP3/Caspase-1/GSDMD axis-drives both the onset and chronicity of PHN. This review outlines the mechanism of action of pyroptosis and its divergent effects in the peripheral versus the central nervous system. Varicella-zoster virus reactivation triggers initial inflammation, promoting NLRP3 inflammasome assembly and Caspase-1 activation. Activated Caspase-1 cleaves GSDMD, resulting in the formation of membrane pores and the release of pro-inflammatory mediators such as IL-1β and IL-18. Peripherally, pyroptosis of satellite glial cells sensitizes sensory neurons through paracrine signaling, leading to peripheral sensitization. Centrally, microglial and astrocytic pyroptosis amplifies neuroinflammation, with the resulting accumulation of reactive oxygen species inducing pyroptosis of GABAergic neurons. The loss of these inhibitory interneurons disrupts the excitatory-inhibitory balance, causing central sensitization. These interconnected processes establish a self-reinforcing inflammation-pyroptosis-pain cycle. Consequently, interventions targeting key pyroptosis nodes-including NLRP3, Caspase-1, GSDMD, and P2X7R-via small-molecule inhibitors, natural compounds, or non-pharmacological approaches such as electroacupuncture, hold significant therapeutic promise for PHN. This review systematically delineates the multifaceted mechanisms underlying the role of pyroptosis in this condition and highlights the therapeutic potential of blocking this pathway to counteract peripheral and central sensitization, thereby offering a novel framework and precision targets for PHN management.