Non-Apoptotic Programmed Cell Death: From Ultrastructural Characterization to Emerging Therapeutic Opportunities

Area of Science:

• Biochemistry and Molecular Biology
• Cell Biology
• Pathology

Background:

• Non-apoptotic programmed cell death (PCD) pathways are crucial in health and disease.
• These pathways, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, cuproptosis, disulfidptosis, and erebosis, have distinct molecular and ultrastructural features.
• Dysregulation of PCD is implicated in various pathologies, including cancer, neurodegeneration, and inflammation.

Purpose of the Study:

• To provide a comprehensive review of distinct non-apoptotic programmed cell death modalities.
• To detail the unique molecular signaling, ultrastructural characteristics, and functional outcomes of each PCD pathway.
• To facilitate the morphological identification of these cell death forms and highlight their therapeutic potential.

Main Methods:

• Literature review and synthesis of existing research on non-apoptotic PCD.
• Detailed characterization of cellular and subcellular hallmarks for each PCD modality.
• Schematic visualization of the identified hallmarks.

Main Results:

• Identification and characterization of multiple non-apoptotic PCD pathways (ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, cuproptosis, disulfidptosis, erebosis).
• Elucidation of distinct molecular signatures and ultrastructural features differentiating these pathways from apoptosis.
• Highlighting the potential of targeting these pathways for therapeutic interventions.

Conclusions:

• Understanding the diverse non-apoptotic PCD pathways is essential for developing novel therapeutic strategies.
• Targeting specific PCD cascades offers promise for overcoming apoptosis resistance in cancer therapy.
• Inhibiting cell death in critical tissues like the myocardium and nervous system is key for cytoprotection in neurodegenerative and inflammatory diseases.