Key Takeaways & Executive Findings
- •• • 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.
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Abstract
Sepsis-associated acute respiratory distress syndrome (ARDS) is driven by alveolar macrophage (AM) pyroptosis and high mobility group box 1 (HMGB1) release, yet therapeutic options remain limited. This study evaluates CDDO-imidazolide (CDDO-Im), a potent Nrf2 activator, in modulating AM pyroptosis and HMGB1 secretion. In vitro, J774A.1 macrophages stimulated with LPS and ATP exhibited NLRP3-mediated pyroptosis and HMGB1 release, which was aggravated by 3-MA inhibition of PINK1/Parkin-dependent mitophagy. CDDO-Im significantly attenuated pyroptosis and HMGB1 release while enhancing PINK1/Parkin mitophagy; these effects were abolished in Nrf2-knockout macrophages. In vivo, caecal ligation perforation (CLP) induced septic ARDS in mice. Intraperitoneal CDDO-Im reduced NLRP3 inflammasome protein expression in lung tissues and HMGB1 levels in serum and bronchoalveolar lavage fluid (BALF). Co-administration of the Nrf2 inhibitor ML385 reversed these protective effects. The data demonstrate that CDDO-Im activates Nrf2, which promotes PINK1/Parkin-mediated mitophagy, thereby suppressing AM pyroptosis and HMGB1 release. This mechanism alleviates sepsis-induced ARDS, offering a potential therapeutic strategy. The study was supported by the National Natural Science Foundation of China (81900081, 82170089), and the authors declare no conflicts of interest.
1. Introduction
Sepsis-associated acute respiratory distress syndrome (ARDS) remains a lethal complication with no targeted pharmacotherapy. Excessive alveolar macrophage (AM) pyroptosis and the subsequent release of high mobility group box 1 (HMGB1) are central to ARDS pathogenesis, yet clinical efforts to inhibit these pathways have largely failed due to poor selectivity, off-target toxicity, or insufficient target engagement. The Nrf2 pathway, a master regulator of antioxidant and cytoprotective responses, has been individually linked to pyroptosis regulation, but its therapeutic potential in sepsis-induced ARDS has not been fully exploited.
This study addresses the bottleneck by employing CDDO-imidazolide (CDDO-Im), a potent and selective Nrf2 activator, to enhance PINK1/Parkin-dependent mitophagy, thereby prohibiting AM pyroptosis and HMGB1 release. Using both in vitro (LPS/ATP-stimulated J774A.1 macrophages, Nrf2-knockout cells) and in vivo (caecal ligation perforation sepsis model, ML385 inhibitor) systems, the authors dissect the mechanism. The findings demonstrate that CDDO-Im significantly reduces NLRP3 inflammasome expression and HMGB1 levels in lung tissues, serum, and BALF, but these effects are reversed by Nrf2 inhibition or knockout. This provides a rigorous mechanistic rationale for targeting the Nrf2-mitophagy axis in sepsis-associated ARDS.
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Yajing Liu, Pengcheng Ye, Cijun Tang, Meiru Jiang, Yiru Shen, Xiangrui Wang, Lei Hou, Yupeng Zhao (2025). CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025092
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Frequently Asked Questions
What is the specific mechanism by which CDDO-imidazolide confers protection against sepsis-induced ARDS?
CDDO-imidazolide activates Nrf2, which in turn enhances PINK1/Parkin-dependent mitophagy. This mitophagy suppresses NLRP3-mediated alveolar macrophage pyroptosis and the subsequent release of HMGB1. In vitro, CDDO-Im significantly increased mitophagy and reduced pyroptosis and HMGB1 release in wild-type macrophages, but these effects were absent in Nrf2-knockout cells. In vivo, CDDO-Im reduced NLRP3 inflammasome protein expression in lung tissues and HMGB1 levels in serum and BALF, effects reversed by the Nrf2 inhibitor ML385.
How robust is the in vivo evidence for the Nrf2-dependent mechanism, and what are the translational implications?
The in vivo data demonstrate that intraperitoneal CDDO-Im before caecal ligation perforation significantly alleviates ARDS pathology, as shown by reduced NLRP3 and HMGB1. However, co-administration of ML385, an Nrf2 inhibitor, completely reversed these protective effects. This indicates that the therapeutic benefit is strictly Nrf2-dependent. For translation, this suggests that patient stratification based on Nrf2 activity may be necessary, and that co-treatment with Nrf2 inhibitors could abrogate efficacy.
What are the limitations of the study regarding the use of a single macrophage cell line and the absence of human data?
The in vitro experiments utilized J774A.1 murine macrophages, which may not fully recapitulate human alveolar macrophage biology. Additionally, the study lacks human clinical samples or ex vivo validation. While the murine CLP model is standard, species differences in Nrf2 signaling and mitophagy regulation could affect translation. The authors acknowledge that additional studies are needed to explore translational potential, and the absence of human data limits direct clinical extrapolation.
What is the role of HMGB1 in sepsis-associated ARDS, and how does CDDO-Im affect its release?
HMGB1 is a pro-inflammatory mediator released during pyroptosis that amplifies lung injury. CDDO-Im significantly inhibited HMGB1 release in the supernatant of LPS/ATP-stimulated macrophages, as well as in serum and BALF of septic mice. This reduction was Nrf2-dependent, as ML385 reversed the effect. The data suggest that targeting HMGB1 release via Nrf2 activation could mitigate the cytokine storm and tissue damage in ARDS.
What are the potential off-target effects or safety concerns of using CDDO-imidazolide, a potent Nrf2 activator, in a clinical setting?
CDDO-Im is a synthetic triterpenoid with known electrophilic properties that can modify cysteine residues beyond Nrf2, potentially affecting other signaling pathways. While the study did not report overt toxicity, the reversal by ML385 indicates on-target Nrf2 effects. However, long-term Nrf2 activation has been linked to oncogenic risks in some contexts. The authors declare no conflicts of interest, but clinical translation would require rigorous safety profiling, especially in sepsis patients with comorbid conditions.
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