This study investigates the role of TFEB in Tuberous Sclerosis Complex (TSC) and its impact on kidney disease. TSC is caused by mutations in TSC1 or TSC2, leading to hyperactivation of mTORC1 and organ lesions. The research shows that TFEB is constitutively active in TSC and is a key driver of renal disease. Two mouse models of TSC were used, with kidney pathology as the primary phenotype. Knockout of TFEB rescued kidney pathology and improved survival, indicating that TFEB is the main driver of renal disease in TSC. Increased mTORC1 activity in TSC2-deficient kidneys was normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increased TFEB phosphorylation and relocalized TFEB to the cytoplasm. Rapamycin treatment normalized lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These findings change the understanding of mTORC1 hyperactivation in TSC and may lead to new therapeutic strategies. The study also highlights the role of TFEB in mTORC1 activation and its impact on kidney disease in TSC, BHD, and translocation RCC. The results suggest that targeting TFEB could be a promising therapeutic approach for TSC-associated renal disease.This study investigates the role of TFEB in Tuberous Sclerosis Complex (TSC) and its impact on kidney disease. TSC is caused by mutations in TSC1 or TSC2, leading to hyperactivation of mTORC1 and organ lesions. The research shows that TFEB is constitutively active in TSC and is a key driver of renal disease. Two mouse models of TSC were used, with kidney pathology as the primary phenotype. Knockout of TFEB rescued kidney pathology and improved survival, indicating that TFEB is the main driver of renal disease in TSC. Increased mTORC1 activity in TSC2-deficient kidneys was normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increased TFEB phosphorylation and relocalized TFEB to the cytoplasm. Rapamycin treatment normalized lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These findings change the understanding of mTORC1 hyperactivation in TSC and may lead to new therapeutic strategies. The study also highlights the role of TFEB in mTORC1 activation and its impact on kidney disease in TSC, BHD, and translocation RCC. The results suggest that targeting TFEB could be a promising therapeutic approach for TSC-associated renal disease.