The Multifaceted Role of Pyroptosis: Molecular Mechanisms, Crosstalk with Other Cell Death Pathways, and Therapeutic Implications

Figures

• 

  FIGURE 1. Homeostatic balance of programmed cell death pathways in human health and disease. Under physiological conditions, regulated programmed cell death (including pyroptosis, apoptosis, necroptosis, and PANoptosis) preserves tissue homeostasis by coordinating cell turnover and immune surveillance. Dysregulation or excessive activation of these pathways disrupts this balance, leading to aberrant cell death, impaired differentiation, chronic inflammation, and disease development, including cancer. Pyroptosis exemplifies how inflammatory cell death can be protective or pathological depending on its molecular control and context.

• 

  FIGURE 2. Canonical, noncanonical, caspase‐dependent, and granzyme‐mediated pathways converge on gasdermin activation to execute pyroptotic cell death. (A) DAMP sensing by inflammasome receptors (NLRP1, NLRP3, NLRC4, AIM2) activates caspase‐1, leading to IL‐1β/IL‐18 maturation and GSDMD‐mediated membrane pore formation. (B) Intracellular LPS activates caspase‐4/5 (caspase‐11 in mice), inducing GSDMD cleavage and pyroptosis, with parallel amplification through NLRP3 inflammasome signaling. (C) Apoptotic or stress stimuli engage Caspase‐8 or Caspase‐3 to cleave GSDMD or GSDME, redirecting apoptosis toward inflammatory pyroptosis. (D) Cytotoxic lymphocyte‐derived granzymes cleave gasdermins (GSDMB, GSDME) directly or via Caspase‐3, resulting in pore formation and pyroptotic cell death.

• 

  FIGURE 3. Context‐dependent roles of pyroptosis across different cancer types. Proptosis is involved in multiple cancers, where it can either promote tumor progression or enhance antitumor responses depending on cellular context and molecular regulation. Its broad involvement enhances pyroptotic pathways as potential therapeutic targets, while emphasizing the need for further investigation to translate these mechanisms into clinical benefit.