ATG7 drives cell fate decisions in kidney tubule homeostasis and disease

Metabolism and differentiation in the kidney proximal tubule (PT) must be tightly coordinated to maintain homeostasis, yet determinants of metabolic cell-fate decisions remain undefined. Here, we combine model organisms with multi-omics landscapes and human genetics to identify the autophagy enzyme ATG7 as a key metabolic driver of PT-cell fate specialization. In mice, PT-specific deletion of ATG7 forces differentiated cells into anabolic, proliferative states, compromising nutrient reabsorption. Mechanistically, loss of ATG7 impairs clearance of lipid droplets, restricts fatty-acid (FA) metabolism, and depletes energy required for normal PT physiology. In zebrafish pronephros, re-expression of wild-type ATG7 rescues reabsorption in atg7 mutants, whereas inhibiting FA oxidation triggers dysfunction. In humans, ATG7 variants associate with cardio-kidney-metabolic health and increased disease risk, whereas low ATG7 levels predict poor survival in clear cell renal carcinoma. These findings establish a conserved paradigm coupling ATG7/autophagy and metabolism to epithelial cell-fate decisions, thus carrying implications for health and disease.