Investigating the Multiple Regulatory Mechanisms and Therapeutic Targets of PHLDA1 in Neurological Diseases.

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PHLDA1 (pleckstrin homology-like domain family A member 1) is a pleiotropic regulatory protein that affects key biological processes such as apoptosis, pyroptosis, immune inflammation, autophagy, metabolism, and oxidative stress. PHLDA1 plays a significant role in the pathological mechanisms of neurological diseases. This article systematically reviews the molecular characteristics of PHLDA1 and its core role in cerebrovascular diseases such as cerebral ischemia/ reperfusion injury, cerebral hemorrhage, subarachnoid hemorrhage, epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Studies have shown that PHLDA1 promotes disease progression by regulating signalling pathways such as the NF-κB, MAPK, NLRP3 inflammasome, PPARγ, and Nrf2 pathways, thereby exacerbating neuroinflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and pyroptosis in neurons. Its expression is regulated by the dynamic balance of miRNAs (such as miR-194 and miR-101), transcription factors (Egr1 and BHLHE40), and heat shock proteins (HSPs/HSF1). In addition, PHLDA1 has become a potential target for intervention in neurodegenerative and ischemic injuries by inhibiting FundC1-mediated mitochondrial autophagy, regulating microglial polarization, and activating TRAF6-dependent neuroinflammation. This article not only clarifies the pathogenic mechanism of PHLDA1 but also summarizes the relevant intervention strategies targeting PHLDA1, hoping to provide a corresponding theoretical basis and reference for the development of precision therapies for neurological diseases.

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