Novel targets for treating neurodegenerative diseases: The PKM2-STAT3-hnRNPA1 feedback loop

Neurodegenerative diseases, such as Alzheimer's disease (AD), typically have an insidious onset and unclear aetiology and are characterized mainly by progressive cognitive decline and behavioural impairments. Currently, interactions among genetic factors, environmental factors, oxidative stress, mitochondrial dysfunction, neuroinflammation, and impaired energy metabolism are the most common pathophysiological mechanisms underlying neurodegenerative diseases. Pyruvate kinase M2 (PKM2), a key enzyme involved in glycolysis, has both metabolic and nonmetabolic functions; signal transducer and activator of transcription 3 (STAT3) is the core of the JAK-STAT inflammatory signalling pathway, which is involved in the transcriptional regulation of many target genes; and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), an RNA-binding protein, regulates RNA posttranscriptional processing and other processes. In recent years, increasing evidence has suggested that hnRNPA1, STAT3 and PKM2 are interrelated and interact with each other. The formation of the PKM2-STAT3-hnRNPA1 feedback loop plays a key role in cellular metabolism, the inflammatory response, cell survival and gene expression regulation, and its aberrant activation is closely related to the occurrence and development of a variety of central nervous system diseases. Focusing on the molecular mechanism of PKM2-STAT3-hnRNPA1 feedback loop formation, we reveal how the three interact and regulate each other at the molecular level, with an emphasis on their pathophysiological roles in AD-dominated neurodegenerative diseases. These findings will contribute to the identification of potential therapeutic targets in neurodegenerative diseases.