Research Progress in Structural Biology of the MIT/TFE/USF Transcription Factor Family and Development of Small Molecule Inhibitors

Min Fang; Mingyu Xia; Zilu Wang; Biao Yu; Pengfei Fang; Jing Wang

doi:10.7536/PC20251216

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Prog Chem ›› 2026, Vol. 38 ›› Issue (6) : 1007-1024. DOI: 10.7536/PC20251216

Review

Research Progress in Structural Biology of the MIT/TFE/USF Transcription Factor Family and Development of Small Molecule Inhibitors

Min Fang ¹^,² ,
Mingyu Xia ² ,
Zilu Wang ² ,
Biao Yu ²^,³^,^* ,
Pengfei Fang ²^,³^,^* ,
Jing Wang ²^,³^,^*

Author information +

History +

Abstract

The microphthalmia/transcription factor E（MiT/TFE）and upstream stimulating factors（USFs）subfamilies be-long to the basic Helix-Loop-Helix Leucine zipper（bHLH-LZ）transcription factor superfamily，serving as key hubs regulating cellular physiological homeostasis and disease progression. The MiT/TFE family comprises four members，namely MITF，TFE3，TFEB，and TFEC，with a signature structural feature of three amino acid insertions in the Leucine zipper（LZ）domain，enabling the formation of dynamic dimers. This family regulates cellular metabolic stress and tissue-specific functions through the autophagy-lysosome pathway. The USFs family includes two members，USF1 and USF2，which rely on stable tetrameric conformations mediated by the LZ-Ext module to enhance transcriptional efficiency via DNA looping，thereby participating in basic transcriptional regulation and maintenance of multi-system homeostasis. Dysfunction of both families is closely associated with cancer，metabolic diseases，immune disorders，and other conditions，and their unique structural domains provide important targets for targeted therapy. This review systematically summarizes the discovery history，member characteristics，structure-function relationships，and pathological significance of the MiT/TFE and USFs families，focuses on the development strategies and progress of small-molecule inhibitors，and finally prospects the future research directions and clinical transformation potential of this field，aiming to provide a theoretical basis and innovative ideas for the precision medicine practice of related diseases.

Contents

1 Introduction

1.1 Discovery and member overview

1.2 Overview of physiological functions and pathological significance

2 Structure and function

2.1 Structure and spatial conformation of MiT/TFE family proteins

2.2 Structure and spatial conformation of USFs family proteins

2.3 The regulatory significance of structural features on functions

3 Development strategies and progress of small molecule inhibitors

3.1 Direct targeting strategy

3.2 Indirect regulation strategy

3.3 Combined treatment strategy

3.4 Emerging targeted protein degradation strategies

4 Conclusion and outlook

Key words

MiT/TFE / USFs / transcription factor / protein structure / small molecule inhibitors / cancer

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Min Fang , Mingyu Xia , Zilu Wang , et al . Research Progress in Structural Biology of the MIT/TFE/USF Transcription Factor Family and Development of Small Molecule Inhibitors[J]. Progress in Chemistry. 2026, 38(6): 1007-1024 https://doi.org/10.7536/PC20251216

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Funding

Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1040000)

National Natural Science Foundation of China(22322706)

National Natural Science Foundation of China(22277134)

National Natural Science Foundation of China(82441039)

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