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Forced expression of uncoupling protein 1 (UCP1) counteracts the compromised activity of NK cells by tumor microenvironment

ABSTRACT: Uncoupling protein 1 (UCP1) is a mitochondrial inner membrane protein whose main function is to mediate non-shivering thermogenesis. Dysregulated expression of UCP1 contributes to the pathogenesis of multiple diseases, including cancer. Natural killer (NK) cells, key effectors of antitumor immunity, are substantially impaired in the tumor microenvironment (TME). Here, we showed that UCP1 expression is markedly downregulated in tumor-infiltrating NK (TINK) cells from both colorectal cancer (CRC) patients and tumor-bearing mice and is correlated with impaired effector function. In the TME, TGF-β1 and hypoxia repress the transcription of UCP1 through the downregulation of C/EBPβ. NK cell-specific ablation of UCP1 accelerated tumor growth and reduced the infiltration of TINKs. RNA sequencing revealed an increase in NLRP3 inflammasome-mediated pyroptosis in Ucp1–/– NK cells. UCP1 deficiency synergized with TME stress to increase the uptake of fatty acids and oxidative phosphorylation via the upregulation of CD36/FABP4. This induces mitochondrial damage and excessive release of mitochondrial DNA (mtDNA), triggering the activation of the NLRP3 inflammasome and NK cell pyroptosis. Enforced UCP1 expression in NK cells prevents TME-induced pyroptosis, maintains the antitumor activity in both murine models and patient-derived organoids. Genetically modified expression of UCP1 in NK cells is a potential therapy for patients with tumors.

ORGANISM(S): Mus Musculus

SUBMITTER: Weijuan Gong

PROVIDER: PXD078876 | iProX | Tue May 26 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

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Forced expression of uncoupling protein 1 (UCP1) counteracts the compromised activity of NK cells by tumor microenvironment

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