The pathological features of regulated necrosis

Area of Science:

• Pathology
• Molecular Biology
• Cell Death Research

Background:

• Cell necrosis is characterized by plasma membrane integrity loss and presents diverse morphological forms.
• Biochemically, necrosis involves genetically determined signaling pathways including necroptosis, pyroptosis, and ferroptosis.
• Current diagnostic methods often rely on morphology, lacking specificity for underlying molecular mechanisms.

Purpose of the Study:

• To highlight the molecular mechanisms of regulated necrosis.
• To introduce novel detection methods for specific necrosis pathways.
• To emphasize the clinical and diagnostic implications of these advancements for pathologists.

Main Methods:

• Utilized immunohistochemistry and immunofluorescence with antibodies against phosphorylated MLKL for necroptosis detection.
• Developed cleavage-specific antibodies for gasdermin family members in pyroptosis.
• Employed mass spectrometry (oxylipidomics) for quantifying oxidative lipids in ferroptosis.
• Integrated these with classical cell death markers like TUNEL and cleaved caspase-3.

Main Results:

• Established specific detection methods for necroptosis (pMLKL antibodies) and ferroptosis (oxylipidomics).
• Demonstrated the feasibility of detecting pyroptosis via gasdermin cleavage-specific antibodies.
• Showcased the potential to correlate molecular pathway detection with morphological features of necrosis.

Conclusions:

• Novel markers allow for the specific pathological detection of molecular necrosis pathways, moving beyond descriptive morphology.
• These advancements are crucial for understanding and treating diseases involving regulated cell death.
• Pathologists should adopt these ancillary tests to improve diagnostic precision, prognostication, and prediction of therapeutic response to novel anti-necrotic agents.