Autophagy regulator ATG7 links energy metabolism to tubular cell fate specialization and kidney disease

Homeostasis in the kidney proximal tubule (PT) requires coordination between metabolism and differentiation, yet the mechanisms governing this balance remain elusive. Here, we integrate model organisms, multiomics profiling, and human genetics to identify the autophagy regulator ATG7 as a key determinant of cell-fate decisions, sustaining PT specialization in health and contributing to dysfunction in disease. In mice, PT-specific deletion of ATG7 reprograms differentiated cells into anabolic, proliferative states, impairing their specialized function and causing kidney tubulopathy. Mechanistically, loss of ATG7-dependent autophagy hinders lipid droplet clearance and restricts fatty-acid oxidation (FAO), leading to energy depletion and functional decline. In zebrafish pronephros, re-expression of wild-type ATG7 restores homeostasis in atg7 mutants, while pharmacological FAO inhibition triggers dysfunction. In humans, ATG7 variants associate with cardio-renal-metabolic traits and increased disease risk, whereas low ATG7 expression correlates with transcriptional signatures of metabolic reprogramming, loss of epithelial markers, and poor prognosis in renal cell carcinoma. These findings establish a conserved genetic paradigm that links autophagy to kidney epithelial cell-fate specialization, with implications for disease, cancer, and metabolic health.