Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury.
Summary
GSDMD is essential for PANoptosis-driven organ injury in heat stress and sepsis models. The small molecule JX06 covalently modifies GSDMD (Cys39/192), prevents GSDMD-NT pore formation, and reduces inflammation, MODS, and mortality in vivo.
Key Findings
- GSDMD deficiency attenuates cell death, inflammation, and multiple organ injury in heat stress and sepsis models.
- JX06 covalently modifies GSDMD at Cys39/192, preventing GSDMD-NT accumulation and pore formation.
- In vivo JX06 suppresses GSDMD-mediated PANoptosis, reducing MODS severity and mortality.
Clinical Implications
GSDMD inhibition could become a targeted adjunctive therapy for sepsis-related MODS, but requires optimization of PK/PD, toxicity, and efficacy across clinically relevant sepsis phenotypes.
Why It Matters
This work provides pharmacologic proof-of-concept that directly targeting GSDMD can suppress PANoptosis and ameliorate MODS, opening a tractable therapeutic avenue for sepsis.
Limitations
- Preclinical modeling without human clinical validation; unknown off-target risks and long-term safety.
- Pharmacokinetic/pharmacodynamic properties and dosing windows require optimization.
Future Directions
Advance JX06 analogs with optimized PK/PD and safety; evaluate efficacy across sepsis phenotypes and comorbidities; identify biomarkers for patient stratification.
Study Information
- Study Type
- Case-control
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical mechanistic and therapeutic study in animal models without human outcomes.
- Study Design
- OTHER