Targeting gasdermin D-mediated pyroptosis: a precision anti-inflammatory strategy for acute and chronic lung diseases.

Summary

This critical review positions gasdermin D as a convergent effector of pyroptosis driving lung inflammation across ARDS and chronic diseases, detailing canonical/noncanonical activation, barrier injury, and cytokine release. It systematically evaluates inhibitors of GSDMD pore formation and upstream caspases, arguing that terminal-pathway targeting may preserve upstream immune sensing compared with broad immunosuppression.

Key Findings

• GSDMD is the key executioner of pyroptosis activated by canonical (caspase-1) and noncanonical (caspase-4/5/11) inflammasomes.
• Pyroptosis drives IL-1β/IL-18 release, immune cell infiltration, endothelial/epithelial barrier disruption, and tissue remodeling in lung diseases including ARDS.
• Therapeutic strategies include direct GSDMD pore inhibitors (disulfiram, necrosulfonamide) and upstream caspase inhibitors (e.g., VX-765), plus phytochemicals.
• Targeting terminal pyroptotic signaling may reduce inflammation while preserving upstream pathogen recognition compared with broad immunosuppression.

Clinical Implications

Encourages biomarker-driven trials of GSDMD or caspase inhibitors in ARDS and other inflammatory lung diseases, with careful safety monitoring to avoid impairing host defense.

Limitations

• Evidence base largely preclinical; paucity of clinical trials in ARDS
• Potential publication bias and heterogeneity across models and readouts

Future Directions

Develop translational studies with pharmacodynamic biomarkers of pyroptosis, assess safety of chronic/acute inhibition, and define clinical endpoints for ARDS trials.