Pyroptosis in Peripheral Neuropathy: From Molecular Mechanisms to Therapeutic Targeting

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Peripheral neuropathy (PN) presents significant treatment challenges.
• Pyroptosis, a form of programmed cell death (PCD), contributes to PN pathogenesis.
• Understanding pyroptosis in PN is crucial for developing new therapies.

Purpose of the Study:

• To review the current understanding of pyroptosis in peripheral neuropathy.
• To evaluate preclinical therapeutic strategies targeting pyroptosis for PN.
• To identify knowledge gaps and future research directions in PN pyroptosis.

Main Methods:

• Systematic literature search of major scientific databases (PubMed, Scopus, Web of Science, Google Scholar).
• Inclusion of original studies investigating pyroptosis in peripheral neuropathy.
• Consolidation and analysis of existing evidence on pyroptosis mechanisms and therapeutic targets in PN.

Main Results:

• Pyroptosis has a context-dependent dual role in PN: detrimental in chronic pain and beneficial in neuroblastoma.
• Canonical and noncanonical pyroptosis pathways, often inflammasome-initiated, are implicated in PN pathogenesis.
• Preclinical studies show promise for pyroptosis inhibitors (e.g., MCC950, VX-765) in alleviating PN pain and promoting nerve repair.
• Emerging concepts like PANoptosis and the roles of various gasdermins in PN require further investigation.
• A significant translational gap exists, with no current clinical trials targeting pyroptosis for PN.

Conclusions:

• Targeting pyroptosis represents a novel therapeutic avenue for peripheral neuropathy.
• Further research is needed to elucidate gasdermin diversity and validate PANoptosis in PN.
• Bridging the translational gap is essential to apply pyroptosis-targeting strategies for PN patients.