Nature | 焦亡通路上的“借道入胞”——GSDMD孔介导的caspase抑制剂靶向递送

TL;DR - A Nature study developed poorly membrane-permeable caspase inhibitors that enter pyroptotic cells through transient GSDMD pores, selectively suppressing inflammatory cell death while sparing apoptosis. The approach could enable safer anti-inflammatory therapies, although liver-enzyme elevations indicate further optimization is needed.

• Screening identified selective covalent inhibitors of inflammatory caspases, including KGR-3 for human caspase-1/4 and KGR-53P for mouse caspase-1/11.
• The inhibitors required GSDMD pores to enter cells, blocking pyroptosis and IL-1β/IL-18 release without disrupting apoptotic pathways.
• Delayed treatment remained effective, showing a therapeutic window after initial GSDMD pore formation.
• KGR-53P reduced inflammatory cytokines in a mouse endotoxin-shock model but raised liver enzymes without LPS, suggesting off-target toxicity.