GL-V9 inhibits Caspase-11 activation-induced pyroptosis by suppressing ALOX12-mediated lipid peroxidation to alleviate sepsis.

Summary

Using CLP mice and macrophage models, the authors show that GL‑V9 suppresses Caspase‑11–dependent pyroptosis by inhibiting ALOX12-mediated lipid peroxidation, reducing inflammation and mortality. Loss of effect in Alox12-deficient mice provides genetic epistasis supporting the mechanism.

Key Findings

• GL‑V9 reduced tissue injury and mortality in CLP-induced murine sepsis.
• GL‑V9 suppressed Caspase‑11–induced pyroptosis and prevented LPS release from early endosomes in macrophages.
• Mechanistically, GL‑V9 inhibited ALOX12-mediated lipid peroxidation; no added benefit was seen in Alox12-deficient mice.

Clinical Implications

While preclinical, the data nominate ALOX12 and the Caspase‑11 pathway as targets for anti-pyroptotic therapy; translational work should evaluate safety, PK/PD, and infection control in human sepsis.

Limitations

• Preclinical study without human subjects; translatability is unproven
• Pharmacokinetics, safety, and spectrum against diverse pathogens not addressed

Future Directions

Assess GL‑V9 and ALOX12 inhibition in large animal sepsis models; delineate off-target effects; and develop clinical candidates with optimized PK/PD profiles.