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This research aims to clarify how IL-27 affects macrophage ferroptosis and its role in sepsis-induced ARDS.

March 4, 2026Open Access

IL-27 Aggravates Sepsis-Induced ARDS by Driving Macrophage Ferroptosis Through Activation of NCOA4-Mediated Ferritinophagy

Key Points

This research aims to clarify how IL-27 affects macrophage ferroptosis and its role in sepsis-induced ARDS.
Used wild-type and IL-27 receptor knockout mice in a sepsis model via cecal ligation and puncture (CLP).
Divided post-model mice into four treatment groups for analysis of IL-27 effects.
Conducted in vitro experiments with RAW 264.7 cells and bone marrow-derived macrophages.
Analyzed the impact of IL-27 and the NCOA4 degrader CV3 on macrophage responses and inflammatory markers.
IL-27 exacerbated macrophage ferritinophagy and ferroptosis, as well as septic lung injury.
Found that NCOA4-mediated ferritinophagy was enhanced, leading to M1 macrophage polarization and increased inflammation.
CV3 effectively reduced ferritinophagy, ferroptosis, and lung inflammation in murine models, demonstrating its therapeutic potential.

Abstract

Background: Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS. Methods: This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R −/− ) mice to establish a cecal ligation and puncture (CLP)-induced sepsis model. The post-modeling mice were randomly divided into four groups: control group, CLP model group, IL-27 combined with CLP treatment group, and IL-27+CLP+PROTAC NCOA4 degrader-1 (Compound V3, CV3) combined treatment group. For the in vitro experiments using RAW 264.7 cells and Bone Marrow-Derived Macrophages (BMDMs), the cells were divided into four main groups as follows: the control group, the lipopolysaccharide (LPS) model group, the LPS+IL-27 treatment group, and the LPS+IL-27+CV3 combination treatment group. Results: This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R −/− mice were resistant to IL-27-induced exacerbation of ferritinophagy and lung injury, confirming the specificity of IL-27 signaling. Conclusion: These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation. Keywords: sepsis, ARDS, macrophage polarization, IL-27, ferritinophagy, NCOA4, FTH1

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