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      Biological and pharmacological roles of pyroptosis in pulmonary inflammation and fibrosis: recent advances and future directions

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          Abstract

          Pyroptosis, an inflammatory regulated cell death (RCD) mechanism, is characterized by cellular swelling, membrane rupture, and subsequent discharge of cellular contents, exerting robust proinflammatory effects. Recent studies have significantly advanced our understanding of pyroptosis, revealing that it can be triggered through inflammasome- and caspase-independent pathways, and interacts intricately with other RCD pathways (e.g., pyroptosis, necroptosis, ferroptosis, and cuproptosis). The pathogenesis of pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, involves a multifaceted interplay of factors such as pathogen infections, environmental pollutants, genetic variations, and immune dysfunction. This chronic and progressive interstitial lung disease is characterized by persistent inflammation, extracellular matrix (ECM) accumulation, and fibrotic alveolar wall thickening, which potentially contribute to deteriorated lung function. Despite recent advances in understanding pyroptosis, the mechanisms by which it regulates PF are not entirely elucidated, and effective strategies to improve clinical outcomes remain unclear. This review strives to deliver a comprehensive overview of the biological functions and molecular mechanisms of pyroptosis, exploring its roles in the pathogenesis of PF. Furthermore, it examines potential biomarkers and therapeutic agents for anti-fibrotic treatments.

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          Most cited references153

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

            Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.
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              Ferroptosis: mechanisms, biology and role in disease

              The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
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                Author and article information

                Contributors
                yixianghu@hnu.edu.cn
                nspdoctor@sr.gxmu.edu.cn
                Journal
                Cell Commun Signal
                Cell Commun Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                5 December 2024
                5 December 2024
                2024
                : 22
                : 586
                Affiliations
                [1 ]GRID grid.67293.39, Department of Clinical Pharmacy, , Xiangtan Central Hospital (The Affiliated Hospital of Hunan University), ; Xiangtan, 411100 China
                [2 ]GRID grid.488482.a, ISNI 0000 0004 1765 5169, Department of Pharmacy, , People’s Hospital of Ningxiang City, Hunan University of Chinese Medicine, ; Changsha, 410600 China
                [3 ]GRID grid.67293.39, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, School of Biomedical Sciences, , Hunan University, ; Changsha, 410082 China
                [4 ]Department of Breast Surgery, The Second Affiliated Hospital of Guangxi Medical University, ( https://ror.org/051mn8706) Nanning, 530000 China
                Article
                1966
                10.1186/s12964-024-01966-3
                11619304
                39639365
                6a40dbd1-53a4-4ad8-9b64-0f02d8613212
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 8 September 2024
                : 27 November 2024
                Funding
                Funded by: The research project of Chinese Medical Association
                Award ID: Z-2021-46-2101
                Funded by: Hunan Provincial Natural Science Foundation of China
                Award ID: 2021JJ40549
                Funded by: Hunan Provincial Administration of Traditional Chinese Medicine Project
                Award ID: E2023026
                Funded by: National Natural Science Foundation of China
                Award ID: 82303797
                Categories
                Review
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2024

                Cell biology
                pulmonary fibrosis,pyroptosis,inflammation,gasdermin,inflammasome
                Cell biology
                pulmonary fibrosis, pyroptosis, inflammation, gasdermin, inflammasome

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