Targeting the DYNLL2-PAK1 axis inhibits caspase-11-dependent pyroptosis to alleviate sepsis.

Summary

DYNLL2 was identified as a driver of sepsis severity and monocyte expansion; it partners with PAK1 to promote OMV uptake, cytosolic LPS release, and caspase-11/GSDMD-mediated pyroptosis. Pharmacologic disruption with Oroxylin A reduced cytosolic LPS, blunted pyroptosis, improved survival, and mitigated organ injury in murine endotoxemia models.

Key Findings

• DYNLL2 expression is elevated in sepsis and correlates with poor prognosis and monocyte expansion.
• DYNLL2 interacts with PAK1 to promote OMV endocytosis, increasing cytosolic LPS and caspase-11/GSDMD activation.
• Genetic depletion of DYNLL2 or PAK1 suppresses OMV internalization and downstream pyroptosis without reducing bacterial clearance.
• Oroxylin A blocks the DYNLL2–PAK1 interaction, reduces cytosolic LPS, and improves survival and organ injury in murine endotoxemia.

Clinical Implications

While preclinical, targeting DYNLL2–PAK1 could complement antimicrobial therapy by limiting caspase-11-dependent pyroptosis and systemic inflammation without impairing bacterial clearance.

Limitations

• Primary in vivo evidence in endotoxemia rather than polymicrobial sepsis (e.g., CLP).
• No human interventional validation of Oroxylin A safety/efficacy.

Future Directions

Validate the DYNLL2–PAK1 axis in CLP and bacterial sepsis models, delineate pharmacokinetics/toxicology of Oroxylin A, and progress to first-in-human studies with pharmacodynamic biomarkers of pyroptosis.