N6-methyladenosine modification regulates cell death in cognitive impairment

Abstract Neurodegenerative diseases are characterized by a decline in brain structure and function. Their pathology involves multiple cell death pathways, including ferroptosis, cuproptosis, and pyroptosis. These pathways are intricately linked to genes associated with metabolism, antioxidant defense, lipid metabolism, chronic inflammation, and nerve regeneration processes. Key regulators of atypical cell death pathways show aberrant N 6 -methyladenosine modification levels under pathological conditions. As the most abundant and dynamic RNA modification in brain tissue, N 6 -methyladenosine plays crucial functional roles. Notably, there exists an intricate interplay between N 6 -methyladenosine modifications and these cell death pathways, both of which are robustly associated with the pathogenesis of neurodegenerative diseases. However, the molecular mechanisms underlying this association remain unclear. This paper reviews the correlation between N 6 -methyladenosine and various cell death patterns in neurodegenerative diseases, with emphasis on the molecular mechanisms underlying the interaction between N 6 -methyladenosine epigenetic regulation and ferroptosis, cuproptosis, and pyroptosis in cognitive impairment. N 6 - methyladenosine-modified ferroptosis plays an important role in neurodegenerative diseases. There is also a close association between N 6 -methyladenosine modification and key molecules related to cuproptosis, which may promote the deposition of copper in the brain. Chronic inflammation, a hallmark of neurodegenerative diseases, is related to pyroptosis and N 6 -methyladenosine modification. It is widely thought that ferroptosis, cuproptosis, and pyroptosis are interconnected processes that may share a common pathway affecting the pathogenesis of neurodegenerative diseases, and are related to key molecules involved in N 6 -methyladenosine epigenetic modification. This suggests a great potential for future neurodegenerative diseases treatment strategies regulated by N 6 -methyladenosine modification. N 6 -methyladenosine modification plays a dual role in nerve injury and regeneration by dynamically regulating processes such as ferroptosis, cuproptosis, and pyroptosis and their key molecules. It maintains the “death-regeneration” balance in oxidative stress and inflammation while selectively promoting axon regeneration through the modulation of methylases. This mechanism indicates a considerable therapeutic target for neurological disorders.