IL-27 Aggravates Sepsis-Induced ARDS by Driving Macrophage Ferroptosis Through Activation of NCOA4-Mediated Ferritinophagy.
Summary
IL-27 synergizes with LPS to drive NCOA4-mediated ferritinophagy, promoting macrophage ferroptosis, M1 polarization, and inflammatory cytokine release in sepsis-induced ARDS models. A PROTAC-based NCOA4 degrader (CV3) disrupts NCOA4-FTH1 interaction, suppresses ferritinophagy/ferroptosis, and alleviates lung injury while restoring antioxidant defenses in murine models.
Key Findings
- IL-27 synergized with LPS to enhance NCOA4-mediated ferritinophagy, increasing FTH1 degradation and LC3A/B expression.
- Ferritinophagy amplification promoted macrophage ferroptosis, M1 polarization, and inflammatory cytokine release.
- The PROTAC NCOA4 degrader CV3 disrupted NCOA4-FTH1 interaction, inhibited ferritinophagy/ferroptosis, and reduced lung injury in murine sepsis-ARDS.
- CV3 treatment restored antioxidant defenses in septic lung injury models.
Clinical Implications
While preclinical, targeting NCOA4-mediated ferritinophagy or upstream IL-27 signaling could inform future anti-inflammatory/anti-ferroptosis therapies for sepsis-associated ARDS.
Why It Matters
This work links IL-27 signaling to ferritinophagy-driven ferroptosis in sepsis-ARDS and demonstrates therapeutic rescue with a first-in-class PROTAC degrader targeting NCOA4. It identifies a tractable, mechanism-based target with clear translational potential.
Limitations
- Preclinical models without human clinical validation
- Safety, pharmacokinetics, and off-target effects of CV3 remain undefined
Future Directions
Validate IL-27/NCOA4 axis in human biospecimens; optimize and profile CV3 for safety/PK; explore combinatorial strategies with anti-inflammatory or antioxidant therapies.
Study Information
- Study Type
- Preclinical mechanistic experimental study
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical in vivo/in vitro mechanistic data without clinical outcomes
- Study Design
- OTHER