The gasdermin family: emerging therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Language: Английский

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Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 9, 2024

Abstract Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents promising target for treating hematologic and solid tumors. However, it is unknown whether the activated in ATC, anti-cancer effects mechanism of action its inhibitor, ruxolitinib (Ruxo, clinical JAK1/2 inhibitor), remain elusive. Our data indicated that signaling significantly upregulated ATC tumor tissues than normal papillary cancer tissues. Apoptosis GSDME-pyroptosis were observed cells following vitro vivo administration Ruxo. Mechanistically, Ruxo suppresses phosphorylation STAT3, resulting repression DRP1 transactivation causing mitochondrial fission deficiency. This deficiency essential activating caspase 9/3-dependent apoptosis GSDME-mediated pyroptosis within cells. In conclusion, our findings indicate directly regulated transactivated by STAT3; this exhibits novel crucial aspect on regulation dynamics. transcriptional inhibition hampered division triggered through mechanisms. These results provide compelling evidence potential therapeutic effectiveness ATC.

Language: Английский

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GSDMD and GSDME synergy in the transition of acute kidney injury to chronic kidney disease

Nephrology Dialysis Transplantation, Journal Year: 2024, Volume and Issue: 39(8), P. 1344 - 1359

Published: Jan. 19, 2024

ABSTRACT Background and hypothesis Acute kidney injury (AKI) could progress to chronic disease (CKD) the AKI-CKD transition has major clinical significance. A growing body of evidence unveiled role pyroptosis in injury. We postulate that GSDMD GSDME exert cumulative effects on by modulating different cellular responses. Methods established an model induced folic acid wildtype (WT), Gsdmd−/−, Gsdme−/−, Gsdmd−/−Gsdme−/− mice. Tubular injury, renal fibrosis inflammatory responses were evaluated. In vitro studies conducted investigate interplay among tubular cells, neutrophils, macrophages. Results Double deletion Gsdmd Gsdme conferred heightened protection against AKI, mitigating responses, including formation neutrophil extracellular traps (NETs), macrophage polarization differentiation, ultimately fibrosis, compared with mice single either or Gsdme. Gsdme, but not deficiency, shielded cells from pyroptosis. GSDME-dependent cell death stimulated NETs prompted towards a pro-inflammatory phenotype. deficiency suppressed subsequently hindered NETs-induced macrophage-to-myofibroblast (MMT). Conclusion collaborate contribute AKI subsequent acid. Synchronous inhibition be innovative therapeutic strategy for transition.

Language: Английский

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Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(7), P. 2815 - 2853

Published: April 24, 2024

Regulated cell death (RCD) is a controlled form of orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, modulating immunity. Accumulating evidence has recently revealed that evasion frequently the primary cause tumor survival. Several have garnered attention promising cancer therapies due their ability induce regression prevent relapse, comparable apoptosis. Moreover, they offer potential solutions for overcoming acquired resistance tumors toward drugs. With an increasing understanding underlying mechanisms governing these subroutines, growing number small-molecule compounds targeting single multiple pathways been discovered, providing novel strategies current therapy. In this review, we comprehensively summarized regulatory emerging mainly including autophagy-dependent death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic NETotic lysosome-dependent immunogenic (ICD). Furthermore, focused on discussing related compounds. brief, insightful findings may provide valuable guidance investigating individual collaborative approaches towards different ultimately driving discovery target significantly enhance future therapeutics.

Language: Английский

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Cell death shapes cancer immunity: spotlighting PANoptosis

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: June 15, 2024

Abstract PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements pyroptosis, apoptosis, and necroptosis. is governed by newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each these PCD types individually, still in early stages research warrants further exploration its specific regulatory mechanisms primary targets. In this review, we provide brief overview conceptual framework molecular components PANoptosis. addition, highlight recent advances understanding therapeutic applications By elucidating crosstalk between apoptosis necroptosis summarizing functional consequences special focus on tumor immune microenvironment, review aims to theoretical basis for potential application cancer therapy.

Language: Английский

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Inhibition of the Sp1/PI3K/AKT signaling pathway exacerbates doxorubicin-induced cardiomyopathy

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: unknown, P. 119960 - 119960

Published: April 1, 2025

Language: Английский

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Recent advances in natural compounds inducing non-apoptotic cell death for anticancer drug resistance

Cancer Drug Resistance, Journal Year: 2023, Volume and Issue: 6(4), P. 709 - 27

Published: Oct. 16, 2023

The induction of cell death is recognized as a potent strategy for cancer treatment. Apoptosis an extensively studied form death, and multiple anticancer drugs exert their therapeutic effects by inducing it. Nonetheless, apoptosis evasion hallmark cancer, rendering cells resistant to chemotherapy drugs. Consequently, there growing interest in exploring novel non-apoptotic forms such ferroptosis, necroptosis, pyroptosis, paraptosis. Natural compounds with properties have garnered significant attention due advantages, including reduced risk drug resistance. Over the past two decades, numerous natural been discovered anti-resistance triggering these four mechanisms. This review primarily focuses on mechanisms recent advancements overcoming resistance Meanwhile, it highlights role effectively addressing through death.

Language: Английский

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Conjugates of 3,5-Bis(arylidene)-4-piperidone and Sesquiterpene Lactones Have an Antitumor Effect via Resetting the Metabolic Phenotype of Cancer Cells

Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2765 - 2765

Published: June 11, 2024

In recent years, researchers have often encountered the significance of aberrant metabolism tumor cells in pathogenesis malignant neoplasms. This phenomenon, known as Warburg effect, provides a number advantages survival neoplastic cells, and its application is considered potential strategy search for antitumor agents. With aim developing promising platform designing therapeutics, we synthesized library conjugates 3,5-bis(arylidene)-4-piperidone sesquiterpene lactones. To gain insight into determinants biological activity prepared compounds, showed that lactones, which are cytotoxic agents, demonstrate selective toward cell lines with glycolysis-inhibiting ability. Moreover, results molecular silico screening allowed us to identify these compounds inhibitors pyruvate kinase M2 oncoprotein, rate-determining enzyme glycolysis. Thus, our work indicate lactones can be agents against glycolysis process, opens new possibilities involved therapeutics among containing piperidone platforms.

Language: Английский

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Hormonal orchestra: mastering mitochondria's role in health and disease

Endocrine, Journal Year: 2024, Volume and Issue: 86(3), P. 903 - 929

Published: Aug. 22, 2024

Language: Английский

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Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 20, 2024

Abstract Pyroptosis, a novel type of programmed cell death (PCD), which provides feasible therapeutic option for the treatment tumors. However, due to hypermethylation promoter, critical protein Gasdermin E (GSDME) is lacking in majority cancer cells, cannot start pyroptosis process and leads dissatisfactory effects. Additionally, quick clearance, systemic side effects, low concentration at tumor site conventional reagents restrict their use clinical therapy. Here, we described combination therapy that induces via ultrasound-targeted microbubble destruction (UTMD) with DNA demethylation. The combined application UTMD hydralazine-loaded nanodroplets (HYD-NDs) can lead rapid release HYD (a demethylation drug), cause up-regulation GSDME expression, produce reactive oxygen species (ROS) by cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs ultrasound (US) group had strongest inhibition effect, rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US 32.73%±7.72%), indicating strategy more significant synergistic anti-tumor effect. In addition, as new drug delivery carrier, have great biosafety, targeting, imaging performance. According results, reasonably regulated pyroptosis, offered optimizing GSDME-silenced solid

Language: Английский

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