Pyroptosis and Cellular Stress: Emerging Mechanisms and Therapeutic Targets

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 28 February 2026 | Viewed by 613

Special Issue Editor


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Guest Editor
1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
2. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA
Interests: pyroptosis; inflammation; inflammasome; cancer immunotherapy; gasdermin; mitochondria; ROS

Special Issue Information

Dear Colleagues,

This Special Issue, "Pyroptosis and Cellular Stress: Emerging Mechanisms and Therapeutic Targets", will focus on the molecular mechanisms underlying pyroptosis and its intricate relationship with various forms of cellular stress, as well as the therapeutic potential of modulating these pathways in inflammation, cancer, and immune-related diseases.

Pyroptosis is a pro-inflammatory form of programmed cell death driven by gasdermin-mediated membrane pore formation and the release of cytokines such as IL-1β and IL-18. Initially identified as a host defense response to infection, pyroptosis is now recognized as a pivotal mechanism in sterile inflammation, tumor immunity, metabolic disorders, and aging-related conditions. Various cellular stressors—including mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and DNA damage—may initiate or potentiate pyroptotic signaling through inflammasome activation or direct modulation of gasdermin proteins.

Unraveling the molecular crosstalk between cellular stress pathways and pyroptosis is essential for the development of precision therapeutics aimed at modulating inflammatory responses and cell death.

We invite authors to submit original research (basic, translational, or clinical) and review articles on the molecular regulation, pathophysiological roles, and therapeutic targeting of pyroptosis and cellular stress pathways. Potential topics include, but are not limited to:

  • Crosstalk between pyroptosis and cellular stress signaling (ROS, mitochondrial stress, ER stress, etc.);
  • The role of pyroptosis in cancer immunity, infection, inflammatory disease, or aging;
  • Multi-omics and structural studies illuminating pyroptotic mechanisms;
  • Impact of cellular metabolism and immunometabolism on inflammasome activation and pyroptotic responses;
  • Inflammasome-independent pathways of inflammatory cell death and their pathological relevance

Dr. Gang Du
Guest Editor

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Keywords

  • pyroptosis
  • cellular stress
  • ROS
  • programmed cell death
  • gasdermin
  • cytokines
  • inflammation
  • infection
  • cellular metabolism
  • immunometabolism

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Published Papers (1 paper)

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Review

19 pages, 823 KB  
Review
Pyroptosis in Alopecia Areata: Synthesizing Emerging Hypotheses and Charting a Path to New Therapies
by Mateusz Łysek, Justyna Putek, Beata Jastrząb-Miśkiewicz, Jacek C. Szepietowski and Piotr K. Krajewski
Biomedicines 2025, 13(12), 2940; https://doi.org/10.3390/biomedicines13122940 - 29 Nov 2025
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Abstract
Background/Objectives: Alopecia areata (AA) is a common, noncicatricial autoimmune hair loss disorder characterized by relapsing inflammation and breakdown of hair follicle immune privilege. Increasing amounts of evidence suggest that pyroptosis, a lytic and inflammatory form of programmed cell death mediated by gasdermins [...] Read more.
Background/Objectives: Alopecia areata (AA) is a common, noncicatricial autoimmune hair loss disorder characterized by relapsing inflammation and breakdown of hair follicle immune privilege. Increasing amounts of evidence suggest that pyroptosis, a lytic and inflammatory form of programmed cell death mediated by gasdermins and inflammasome activation, may play a role in AA pathogenesis. This review aims to synthesize current data on the molecular mechanisms linking inflammasome-driven pyroptosis with AA and to highlight emerging therapeutic opportunities. Methods: A comprehensive literature review was conducted focusing on mechanistic studies, ex vivo human scalp models, murine AA models, and interventional clinical data. A structured system of Levels of Evidence (LoE) and standardized nomenclature for experimental models was applied to ensure transparency in evaluating the role of pyroptosis and treatment strategies in AA. Results: Available evidence indicates that outer root sheath keratinocytes express functional inflammasome components, including NOD-like receptor family, pyrin domain containing 3 (NLRP3), adaptor-apoptosis-associated-speck-like protein (ASC), and caspase-1, and contribute to interleukin (IL)-1β release and pyroptotic cell death. Mitochondrial dysfunction, mediated by regulators such as PTEN and PINK1, amplifies NLRP3 activation and cytokine secretion, linking mitophagy impairment with follicular damage. Animal and human biopsy studies confirm increased inflammasome activity in AA lesions. Therapeutic approaches targeting pyroptosis include Janus kinase (JAK) inhibitors, biologics, Phosphodiesterase 4 (PDE4) inhibitors, mesenchymal stem cell therapy, natural compounds, and inflammasome inhibitors such as MCC950. While some agents demonstrated efficacy in clinical trials, most strategies remain at preclinical or early clinical stages. Conclusions: Pyroptosis represents a critical mechanism driving hair follicle structural and functional disruption and immune dysregulation in AA. By integrating evidence from molecular studies, disease models, and early clinical data, this review underscores the potential of targeting inflammasome-driven pyroptosis as a novel therapeutic strategy. Full article
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