4-Octyl itaconate-induced Nrf2 nuclear translocation mitigates Caspase-11-dependent noncanonical macrophage pyroptosis and acute lung injury

INTRODUCTION: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions, with mortality rates reaching 40%. A key driver of their pathogenesis is macrophage pyroptosis, which results in excessive inflammation and tissue damage. OBJECTIVES: The aim of this study was to investigate the regulatory effect and underlying mechanism of the itaconate derivative 4-octyl itaconate (4-OI) on macrophage pyroptosis and sepsis-induced ALI/ARDS. METHODS: mice, along with a parallel experiment of DOTAP-transfected LPS. RESULTS: mice and with ML385 revealed that this effect is mediated by Nrf2‑dependent transcriptional inhibition of Casp4. Furthermore, Acod1 deficiency mice exacerbated Caspase‑11‑driven noncanonical pyroptosis. CONCLUSION: The results demonstrate that 4-OI effectively inhibits Caspase-11-mediated pyroptosis and subsequent inflammation in experimental ALI/ARDS. This effect is mechanistically dependent on the activation of the Nrf2-Caspase-11 axis. The study thus identifies a novel therapeutic strategy whereby 4-OI targets pyroptotic pore formation, offering a potential therapeutic intervention for ALI/ARDS.