Pyroptosis mechanism drives postherpetic neuralgia, offering novel therapeutic targets like NLRP3 and Caspase-1.

Postherpetic neuralgia (PHN) is a debilitating and often intractable neuropathic pain condition, representing the most frequent sequela of herpes zoster. Current treatments often provide inadequate relief, highlighting a significant unmet clinical need. Emerging research points to a complex interplay between inflammatory cascades and programmed cell death in PHN pathogenesis. Specifically, pyroptosis—an inflammatory form of cell death—has been identified as a key driver, making its underlying mechanisms and potential therapeutic modulation a critical area of study.

This systematic review synthesized current literature on postherpetic neuralgia (PHN) and its intricate relationship with pyroptosis. Researchers analyzed studies detailing the NLRP3/Caspase-1/GSDMD axis, peripheral sensitization via satellite glial cells, and central sensitization involving microglial, astrocytic, and GABAergic neuron pyroptosis. The review aimed to delineate the multifaceted mechanisms underlying pyroptosis's role in PHN and to identify potential therapeutic targets for its management, encompassing small-molecule inhibitors, natural compounds, and non-pharmacological approaches.

Varicella-zoster virus reactivation triggers initial inflammation, promoting NLRP3 inflammasome assembly and Caspase-1 activation. Activated Caspase-1 then cleaves GSDMD, leading to the formation of membrane pores and the release of potent pro-inflammatory mediators such as IL-1β and IL-18. Peripherally, pyroptosis of satellite glial cells sensitizes sensory neurons through paracrine signaling, contributing 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. This establishes a self-reinforcing inflammation-pyroptosis-pain cycle. Consequently, interventions targeting key pyroptosis nodes—including NLRP3, Caspase-1, GSDMD, and P2X7R—hold significant therapeutic promise for PHN. The review systematically delineates these mechanisms, highlighting the potential of blocking this pathway to counteract both peripheral and central sensitization.