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

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. This work was partly supported by the Beijing-Tianjin-Hebei Basic Research Cooperation Special Project (H2023206902, 23JCZXJC00130 and J230014), Hebei Province Central Leading Local Science and Technology Development Fund Project (246Z7746G), National Natural Science Foundation of China (82171536), and Hebei Provincial Natural Science Foundation Project (H2023206511). These authors contributed equally: Xincheng Li, Yifei Sang.

China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing Key Laboratory of Neurogenic Bladder Diagnosis and Rehabilitation Innovation and Translation, Beijing, 100068, China Hebei Key Laboratory of Early Life Health Promotion (SZX202419), Hebei Medical University, Shijiazhuang, 050031, China Xincheng Li, Yifei Sang, Xiaoyu Liu, Yunluo Li, Qin Wang, Dandan Liu, Yuan Gao, Haishui Shi & Yun Shi Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050017, China Yifei Sang, Qiming Yu, Qin Wang, Dandan Liu, Yuan Gao & Yun Shi School of Nursing, Hebei Medical University, Shijiazhuang, 050031, China Key Laboratory of Vascular Biology of Hebei Province, Shijiazhuang, 050017, China Correspondence to Haishui Shi or Yun Shi. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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