CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release

• • CDDO-Im reduced NLRP3 inflammasome protein expression in lung tissues of septic mice and decreased HMGB1 levels in serum and BALF; however, co-administration of the Nrf2 inhibitor ML385 reversed these effects, confirming Nrf2 dependence. This underscores the clinical requirement for sustained Nrf2 activation to achieve therapeutic benefit. • • In LPS/ATP-stimulated J774A.1 macrophages, 3-MA inhibition of PINK1/Parkin-dependent mitophagy aggravated NLRP3-mediated pyroptosis and HMGB1 release, indicating that intact mitophagy is essential for limiting inflammatory cell death. This highlights mitophagy as a critical checkpoint for ARDS intervention. • • CDDO-Im significantly enhanced PINK1/Parkin-dependent mitophagy and reduced pyroptosis and HMGB1 release in wild-type macrophages, but these effects were absent in Nrf2-knockout cells. This genetic evidence establishes Nrf2 as the obligatory upstream mediator of CDDO-Im's protective actions. • • In vivo, intraperitoneal CDDO-Im before CLP-induced sepsis significantly alleviated ARDS pathology, as evidenced by reduced NLRP3 and HMGB1; however, ML385 reversed these benefits. The data support targeting the Nrf2-mitophagy axis, but also reveal that pharmacological Nrf2 inhibition can abrogate protection, necessitating careful patient selection.