Exploring the roles of AKR1C1, AKR1C2, and AKR1C3 in the nervous system: Mechanisms and perspectives

Abstract

Aldo-keto reductase 1C (AKR1C) enzymes, including AKR1C1, AKR1C2, and AKR1C3, play crucial roles in the metabolism of steroid hormones and prostaglandins through their catalytic activities. Although their functions have been extensively studied in endocrine tissues and hormone-dependent malignancies, their significance in the nervous system remains underexplored. Emerging evidence suggests that AKR1C enzymes regulate neurosteroid homeostasis, modulate GABAergic neurotransmission, support synaptic plasticity, and participate in cellular defense against oxidative stress. These multifaceted activities implicate AKR1C1–C3 in diverse neural processes, including neuroprotection, emotional regulation, and neurodevelopment. Furthermore, the potential involvement of AKR1C1, AKR1C2, and AKR1C3 in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease suggests their possible therapeutic relevance. This review consolidates current findings on the molecular characteristics, brain region-specific expression, and neurophysiological functions of AKR1C enzymes, and discusses their emerging roles in central nervous system disorders. By presenting these insights, this review offers a valuable framework for researchers to explore new directions in the development of neuroprotective and neuroregenerative strategies.