ArticleCell communication and signaling : CCS2023
Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation.
Article in Cell communication and signaling : CCS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 11 citations in OpenAlex.
- Iron-related intercellular communication in the liver: Main players and mechanisms.European journal of clinical investigation · 2026Review
- Optimized detection of caspase-6 activation in a murine inflammation model to inform neurodegenerative disease therapies.PloS one · 2026Article
- Deciphering the NEK7-NLRP3 inflammasome assembly: from conformational activation to allosteric drug discovery.Frontiers in immunology · 2026Review
- The role of programmed cell death in chronic obstructive pulmonary disease: from pathogenesis to treatment.Frontiers in immunology · 2026Review
- Involvement of HMGB1-mediated ferroptosis in systemic diseases.Frontiers in cell and developmental biology · 2025Review
- Recent advances in the interaction of ferroptosis and immune-mediated inflammation in cardiovascular disease: mechanisms and therapeutic potential.Frontiers in immunology · 2025Review
- The assembly and activation of the PANoptosome promote porcine granulosa cell programmed cell death during follicular atresia.Journal of animal science and biotechnology · 2024Article
- PANoptosis: a new insight for oral diseases.Molecular biology reports · 2024Review
- Signaling, cancer cell plasticity, and intratumor heterogeneity.Cell communication and signaling : CCS · 2024Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCaspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury.
methodsHuman liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6
resultsIn human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages.
conclusionsOur findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Video Abstract.
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