Therapeutic targeting of TCF/LEF transcription factors in neuropsychiatric disorders via Wnt/β-catenin signaling

Abstract

The T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family, comprising TCF1, LEF1, TCF7L1, and TCF7L2, serves as nuclear effectors of the canonical Wnt/β-catenin signaling pathway and plays pivotal roles in neurodevelopment, synaptic plasticity, neuroinflammation, and central nervous system homeostasis. Accumulating evidence implicates aberrant TCF/LEF signaling in the pathophysiology of major neuropsychiatric disorders, including major depressive disorder, bipolar disorder, anxiety disorders, schizophrenia, autism spectrum disorder, and Alzheimer’s disease. This review synthesizes current evidence regarding the structural characteristics, spatiotemporal expression patterns, and multifaceted functions of TCF/LEF transcription factors in the brain. We summarize evidence for downstream target gene networks, including neurotrophins, neurotransmitter receptors, ion channels, myelination-related genes, and metabolic regulators, and discuss how dysregulation of these pathways may contribute to disease-related phenotypes. Particular attention is given to TCF7L2, given its convergent roles in neural development, synaptic function, and metabolic integration, and its genetic association with multiple neuropsychiatric conditions. We further evaluated emerging therapeutic strategies targeting the Wnt/β-catenin/TCF axis, including GSK-3β inhibitors, repurposed drugs, and potential biomarkers for patient stratification. By integrating molecular, genetic, and preclinical evidence, this review highlights the TCF/LEF family as potential therapeutic nodes and candidate biomarkers, while outlining key knowledge gaps and future directions for the translation of these findings into precision psychiatry.