Pyroptosis in Peripheral Neuropathy: From Molecular Mechanisms to Therapeutic Targeting

TL;DR

Pyroptosis, an inflammatory cell death process, plays both harmful and helpful roles in peripheral neuropathy, offering new treatment possibilities.

Contribution

This is the first comprehensive review focusing on pyroptosis in peripheral neuropathy, highlighting its dual role and therapeutic potential.

Findings

Pyroptosis contributes to neuropathic pain through inflammasome pathways like NLRP3 and caspase/GSDM complexes.

Pyroptosis can be beneficial in neuroblastoma by inducing tumor cell death.

Preclinical inhibitors of pyroptosis show promise in pain relief and nerve repair, but clinical trials are lacking.

Abstract

Peripheral neuropathy (PN) is a common consequence of peripheral nervous system (PNS) disorders, yet its effective treatment remains a significant clinical challenge. Pyroptosis, an inflammatory form of programmed cell death (PCD) triggered by gasdermin A–E (GSDMA‐E), contributes to the pathogenesis of PN and represents a promising therapeutic target. While reviews of pyroptosis in other diseases are extensive, comprehensive reviews focusing on PN are lacking.

We systematically searched PubMed, Scopus, Web of Science, and Google Scholar (1986–2025). Only original studies investigating pyroptosis in PN were included.

This review first consolidates established evidence, highlighting a context‐dependent dual role of pyroptosis in PN. Its detrimental effects in chronic pain involve canonical (caspase‐1/GSDMD) or noncanonical pathways (e.g., caspase‐4/5/11/GSDMD, caspase‐3/GSDME, caspase‐8/GSDMC), often initiated by inflammasomes (e.g., NOD‐like receptor family pyrin domain containing 3 [NLRP3]). Conversely, its beneficial, tumoricidal role is leveraged in neuroblastoma. Preclinically, diverse inhibitors—including NLRP3 inhibitors (e.g., MCC950), caspase‐1 inhibitors (e.g., VX‐765), and P2X7R antagonists (e.g., Brilliant Blue G)—alleviate pain and promote nerve repair, while pyroptosis inducers (e.g., axitinib) combat chemoresistant tumors. We then identify critical knowledge gaps and emerging frontiers. The roles of most gasdermins (GSDMA, GSDMB, GSDMC) in PN are unknown. We explore the emerging concept of PANoptosis (crosstalk among pyroptosis, apoptosis, and necroptosis) as a novel conceptual framework for PNS pathologies, where shared molecular hubs may amplify neuroinflammation. Furthermore, despite promising strategies like combination therapy and drug repurposing, a significant translational gap exists, with no current clinical trials specifically targeting pyroptosis for PN.

Targeting pyroptosis is a novel therapeutic avenue for PN. This review synthesizes current mechanistic understanding, evaluates preclinical therapeutic strategies, and delineates crucial future directions, including elucidating gasdermin diversity, validating PANoptosis, and bridging the translational divide, thereby accelerating their application for patients suffering from PN.

Pyroptosis is a key inflammatory cell death pathway in peripheral neuropathy, with opposing roles: it perpetuates neuropathic pain but can be induced to kill neuroblastoma cells. This review consolidates mechanistic understanding and therapeutic strategies, arguing for a shift from disease‐centric to target‐centric treatment approaches to improve patient outcomes.

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