IL-35 alleviates ferroptosis in macrophage by activating the NRF2/GPX4 pathway to improve sepsis-induced ARDS.

Summary

In LPS-driven macrophages and a murine cecal ligation and puncture model, IL-35 shifted macrophage polarization away from M1 toward M2, activated NRF2/GPX4 signaling, and reduced ferroptosis. NRF2 inhibition abrogated these effects. Co-culture with IL-35–conditioned macrophages reduced apoptosis in lung epithelial cells and increased IL-10, suggesting an immunometabolic mechanism for mitigating sepsis-induced ARDS.

Key Findings

• IL-35 inhibits LPS-induced M1 polarization and promotes M2 phenotype in macrophages (RAW264.7 and BMDMs).
• IL-35 activates NRF2/GPX4 signaling and attenuates macrophage ferroptosis; NRF2 inhibition reverses these effects.
• In a CLP sepsis model, rIL-35 reduces lung injury and ferroptosis markers.
• Co-culture with IL-35–treated macrophages decreases apoptosis of MLE-12 epithelial cells and increases IL-10 expression.

Clinical Implications

While preclinical, IL-35 or strategies boosting NRF2/GPX4 could be explored to attenuate hyperinflammation and ferroptosis in sepsis-induced ARDS; biomarkers along this axis may guide patient selection.

Limitations

• Preclinical study without human data; translational dosing, safety, and pharmacokinetics remain unknown
• Sample sizes and randomization/blinding details are not specified in the abstract

Future Directions

Validate IL-35/NRF2-GPX4 targeting in large-animal models and early-phase trials; define dosing, delivery, safety, and biomarkers for patient stratification.