MiT/TFE (TFEB/TFE3) Pathways in Pulmonary Diseases: Current Evidence and Emerging Mechanisms

The MiT/TFE family transcription factors play a critical role in regulating lysosomal biogenesis, autophagy, mitochondrial turnover and lipid catabolism by regulating the CLEAR gene network. The dysregulation of MiT/TFE activity has been implicated in the onset and progression of cancer and neurodegeneration but its functions in asso-ciation with pulmonary diseases remain poorly understood. Thus, elucidating the role of MiT/TFE proteins in cellular homeostasis in the lung is crucial for understanding the origin and progression of pulmonary diseases such as inflammation, disrupted repair mechanisms, and fibrosis. In this review we systematically summarize the findings from human pulmonary diseases and associated genetic disorders, such as asthma, cancer, Birt-Hogg-Dube (BHD) syndrome, and lung injury models that implicate MiT/TFE dysregulation in pathogenic progression. We also discussed MiT/TFE regula-tion and signaling through pathways involving mTORC1, AMPK, and lysosomal stress in different cellular contexts. Finally, we discussed significant mechanistic gaps, such as the absence of in vivo models targeting the combined activity of TFEB and TFE3 in disease progression and prevention. In conclusion, these insights seek to offer a com-prehensive framework for understanding MiT/TFE signaling in human lung diseases and could present a promising opportunity for directing future mechanistic and translational research.