Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models.

Summary

Genetic deletion or pharmacologic inhibition of PKCα restored hepatic excretory function and improved survival in murine sepsis without impairing pathogen clearance. Repurposing midostaurin, a clinically approved drug, suggests a feasible host-directed strategy for sepsis-associated liver failure.

Key Findings

• PKCα knockout and midostaurin-mediated PKCα inhibition restored hepatic excretory function in murine sepsis.
• Both genetic and pharmacologic approaches significantly improved survival without compromising pathogen clearance.
• Midostaurin reduced plasma bile acids and inflammation in treated patients, supporting translational relevance.

Clinical Implications

If validated clinically, PKCα inhibition (e.g., midostaurin) could become an adjunct to organ support for sepsis-associated liver failure, aiming to restore excretory function without immunosuppression.

Limitations

• Preclinical data; human efficacy in sepsis not demonstrated
• Potential off-target effects of midostaurin and dosing/PK considerations in critically ill patients not addressed

Future Directions

Conduct dose-finding and safety studies of PKCα inhibition in sepsis-associated liver dysfunction, followed by early-phase clinical trials assessing liver function and clinical outcomes.