Pyroptosis Regulated by N6-Methyladenosine Modification: Implications for Pyroptosis-Related Disease Therapy.

BACKGROUND

Pyroptosis is a lytic and inflammatory form of programmed cell death that is typically initiated by inflammasome activation and executed by gasdermin proteins. It is characterized by cellular swelling, plasma membrane perforation, and the release of intracellular contents. Pyroptosis functions as a "double-edged sword" and plays an essential role in defending the host against pathogen invasion when properly regulated; however, excessive or dysregulated pyroptotic activity can contribute to severe inflammatory pathologies. Aberrant pyroptosis is associated with a range of diseases, including sepsis, inflammatory disorders, cancer, atherosclerosis and neurodegenerative disorders. N6-methyladenosine (m6A) modification is among the most abundant and widespread epigenetic modifications in eukaryotic RNAs and influences multiple stages of gene regulation, from messenger RNA processing to protein synthesis. Emerging evidence indicates that m6A modification plays a regulatory role in pyroptosis, suggesting promising avenues for therapeutic intervention in pyroptosis-related diseases.

SUMMARY: This review provides a systematic delineation of the signalling pathways regulating pyroptosis and a comprehensive analysis of how m6A modification dynamically regulates this form of inflammatory cell death through its writer, eraser, and reader proteins and explores potential molecular triggers of disease progression. We further aimed to elucidate the pathophysiological significance of m6A-mediated regulation of pyroptosis in disease and identify novel therapeutic targets.

KEY MESSAGES: (1). Pyroptosis is a "double-edged sword": essential for host defense against pathogens when regulated, but harmful when excessive or dysregulated. (2). M6A modification acts as a critical epigenetic regulator that dynamically controls pyroptosis via writer, eraser and reader proteins. (3). Elucidating the m6A-pyroptosis regulatory axis contributes to understanding disease pathogenesis and facilitates the development of new targeted therapies.