TNF/TNFR1 Signaling Mediates DEHP-Induced Hepatocyte Pyroptosis via the GSDMD–mtROS Axis

Journal of Agricultural and Food Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates humans and animals through the food chain over time, resulting liver toxicity. Recent studies have reported that pyroptosis mitochondrial damage are closely related to a variety of diseases, but specific mechanism still unclear. To address this issue, vitro vivo hepatotoxicity models were established. The results demonstrated exposure DEHP caused buildup MEHP livers, altered metabolite composition, pyroptosis-like changes hepatocytes. After treatment, REDOX homeostasis was unbalanced, reactive oxygen species (mtROS) overproduced. activates mediated by TNF/TNFR1 signaling upregulates perforating protein GSDMD-N destroy membrane Above all, study elucidates potential involvement signaling-mediated confirms regulation helpful maintaining normal function.

Language: Английский

---

Photothermal therapy combined with a STING agonist induces pyroptosis, and gasdermin D could be a new biomarker for guiding the treatment of pancreatic cancer

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 4, 2025

Although photothermal therapy (PTT) can induce antitumour immunity, the mechanisms underlying its effects in pancreatic cancer (PC) require further exploration. In this study, mechanism of action PTT and connection to pyroptosis as well therapeutic potential alone combination with STING agonists, were investigated. addition, a biomarker PC was found stratify patients who are suitable for PTT. We explored whether vitro evaluated efficacy immunity-inducing ability combined agonist (c-di-GMP) immune adjuvant vivo PC. also gasdermin D (GSDMD) expression tumour tissues investigated drug sensitivity patient-derived organoids (PDOs) differential GSDMD expression. Our study demonstrated that local induces via caspase-1/GSDMD pathway elicits immunity. exhibits better than while limiting distant metastasis, enhances response by promoting dendritic cell maturation, increasing frequency infiltrating T cells, converting macrophages from M2 M1 phenotype. we is highly expressed overexpression might suggest increased resistance chemotherapy benefits therapy. confirmed PDOs higher less sensitive chemotherapeutic agent (5-Fluorouracil) lower expression, making new identifying may benefit work, c-di-GMP used an treat first time, results provide clues development novel immunotherapies simultaneously suppress primary tumours metastases. has great selection individualized treatment modalities.

Language: Английский

---

Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(788)

Published: March 5, 2025

Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed GOLPH3L interacted stimulator interferon genes (STING) at aspartic acid residue 184 after RT, leading to coat protein complex II-mediated retrograde transport STING from endoplasmic reticulum. This suppressed STING-NOD-like receptor thermal domain associated (NLRP3)-mediated pyroptosis, resulting suppressive TIME, driving GBM resistance RT. Genetic ablation cells augmented antitumor immunity overcame Moreover, have identified a small molecular inhibitor GOLPH3L, vitamin B5 calcium (VB5), which improved efficacy RT checkpoint blockade inducing robust response mouse models. Clinically, treated VB5 responses Thus, reprogramming TIME targeting may offer potential opportunity improve

Language: Английский

---

Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3321 - 3321

Published: April 2, 2025

Mechanical force regulates tissue remodeling during orthodontic tooth movement (OTM) by inducing macrophage-mediated sterile inflammatory responses. Pyroptosis, as an form of programmed cell death, triggers a robust cascade activating the inflammasome. Although recent reports have demonstrated that pyroptosis can be activated mechanical force, it remains unclear whether and how induces macrophage inflammation. In this study, establishing rat OTM model force-loaded model, we found Caspase1-dependent in macrophages activates inflammation both vivo vitro. Mechanistically, uncovered disrupts energy metabolism, characterized imbalance between lactate dehydrogenase A (LDHA) pyruvate (PDH), well mitochondrial dysfunction. Notably, inhibiting kinase 1 (PDK1) effectively restored metabolic balance, thereby alleviating force-stimulated macrophages. Overall, study elucidates inflammation, further identifies imbalances LDHA/PDH ratio dysfunction pivotal mechanistic features. These insights offer novel perspectives potential therapeutic targets for precise effective modulation OTM.

Language: Английский

---

Toll-Like Receptors, PAMPs, and DAMPs in Hepatotoxicity

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

---