KIAA1199 aggravates sepsis-induced lung injury by promoting complement activation.

Summary

KIAA1199 is elevated in human sepsis and enriched in AT2 cells in septic mouse lungs. AT2-specific KIAA1199 knockout improves survival and attenuates lung injury and cytokines, mechanistically by downregulating CFH via p53 degradation to unleash alternative pathway complement activation.

Key Findings

• Serum KIAA1199 was elevated in sepsis patients and positively correlated with SOFA score.
• KIAA1199 expression increased in septic mouse lungs, especially in AT2 cells.
• AT2-specific KIAA1199 knockout improved survival, reduced lung injury, and lowered proinflammatory cytokines in LPS-induced ALI.
• Mechanism: KIAA1199 downregulated CFH by enhancing ubiquitinated degradation of p53, promoting alternative-pathway complement activation.

Clinical Implications

Therapeutically, modulating KIAA1199 or restoring CFH (e.g., via p53 stabilization) may limit complement-mediated lung injury in sepsis, complementing ventilatory strategies in the ICU.

Limitations

• ALI model based on LPS; generalizability to polymicrobial sepsis and clinical heterogeneity uncertain
• Therapeutic interventions targeting KIAA1199/p53–CFH axis not yet tested in large animals or humans

Future Directions

Develop selective KIAA1199 inhibitors or p53-stabilizing strategies, test in polymicrobial sepsis and ventilation models, and evaluate synergy with complement inhibitors.