ArticleCell death & disease2025
The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Role of PANoptosis in the development of gastric immunity and related gastric mucosal disease (Review).Molecular medicine reports · 2026Review
- RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis.EMBO molecular medicine · 2026Article
- Different Functions of Human Scavenger Receptors BI and BII Overexpressed in a Murine Abdominal Sepsis Model.Biomolecules · 2026Article
- Regulatory interplay between nitric oxide and heme in redox signaling and inflammation.Redox biology · 2026Review
- The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.Cell communication and signaling : CCS · 2026Review
- The Endogenous Metabolite TDCA Ameliorates LPS-Driven Liver Injury via Modulation of Caspase-11/GSDMD-Mediated Pyroptosis.International journal of molecular sciences · 2026Article
- β-Glucan Protects Against Sepsis-Induced Kupffer Cell Loss by Inhibiting Pyroptosis and Promoting Self-Renewal.Immunology · 2026Article
- cGAS-STING and PANoptosis: Interplay, Underlying Mechanisms, and Therapeutic Targets.Drug design, development and therapy · 2026Review
- Drug-resistant bacterial infections in end-stage liver disease: immune imbalance and intervention advances.Frontiers in immunology · 2026Review
- The mechanisms by which free heme exacerbates sepsis and the potential therapeutic targets.Frontiers in immunology · 2026Review
- Heme drives cardiac endothelial senescence in sepsis via STING activation.Cell death & disease · 2025Article
- Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.Apoptosis : an international journal on programmed cell death · 2025Review
- HSPA12B Protects Against Age-Related Endothelial Cell Senescence by Regulating STING Degradation.Aging cell · 2025Article
- High-fat diet activates pyroptosis of retinal pigment epithelial cells in aged TgAPPswePS1 transgenic mice.European journal of medical research · 2025Article
- PANoptosis in urological diseases: molecular mechanisms, pathological roles, and emerging therapeutic opportunities.Frontiers in immunology · 2025Review
- Tracking hemopexin intracellularly and defining hemopexin protein "interactomes" in human immune and liver cell models.Frontiers in physiology · 2025Article
- Targeting PANoptosis in Bacterial-Induced Inflammatory Diseases: Mechanisms and Therapeutic Interventions.Journal of inflammation research · 2025Review
- Crosstalk Between Cell Death and the cGAS-STING Pathway in Sepsis-Associated Acute Lung Injury.Journal of inflammation research · 2025Review
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Authors and funding
13 authors.
Funding
Abstract
Elevated heme levels, a consequence of hemolysis, are strongly associated with increased susceptibility to bacterial infections and adverse sepsis outcomes, particularly in older populations. However, the underlying mechanisms remain poorly understood. Using a cecal ligation and puncture (CLP) model of sepsis, we demonstrate that elevated heme levels correlate with Kupffer cell loss, increased bacterial burden, and heightened mortality. Mechanistically, we identify mitochondrial damage as a key driver of heme- and bacterial-induced Kupffer cell PANoptosis, a form of cell death integrating pyroptosis, apoptosis, and necroptosis, as well as cellular senescence. Specifically, heme activates phospholipase C gamma (PLC-γ), facilitating the translocation of cleaved gasdermin D (c-GSDMD) to mitochondria, resulting in GSDMD pore formation, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA) during bacterial infection. This mitochondrial damage amplifies PANoptosis and triggers the cGAS-STING signaling pathway, further driving immune senescence. Notably, PLC-γ inhibition significantly reduces mitochondrial damage, cell death, and senescence caused by heme and bacterial infection. Furthermore, we show that hemopexin, a heme scavenger, effectively mitigates sepsis-induced Kupffer cell death and senescence, enhances bacterial clearance, and improves survival outcomes in both young and aged mice. These findings establish mitochondrial damage as a central mediator of heme induced Kupffer cell loss and highlight PLC-γ inhibition and hemopexin administration as promising therapeutic strategies for combating sepsis associated immune dysfunction.
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