Figure 1Figure 1
Integrated mechanistic model of MiT-RCC driven by TFE3 and TFEB alterations. In TFE3 -rearranged RCC, most fusions join a 5′ partner gene to the 3′ portion of TFE3 , preserving the C-terminal DNA-binding and dimerization domains and promoting constitutive nuclear activity; TFEB -rearranged tumors are driven by analogous transcriptional deregulation, whereas TFEB -amplified RCC is biologically distinct. These events activate a core MiT/TFE transcriptional program that rewires tumor cell metabolism and stress-adaptation pathways. In fusion-driven translocation RCC (tRCC), TFE3 / TFEB fusions induce upregulation of PPARGC1A (PGC-1α), promoting mitochondrial biogenesis and increased dependency on oxidative phosphorylation (OXPHOS), which creates context-specific metabolic vulnerabilities. In parallel, sustained activation of the mTOR-lysosome axis enhances lysosomal biogenesis and autophagy, supporting tumor survival under metabolic stress and reflecting partial uncoupling of M