Precise coupling between differentiation and metabolism in the kidney proximal tubule (PT) is critical for homeostasis, yet determinants of tubular cell fate specialization remain unclear. Using genetically engineered model organisms, cell cultures, proteomic and metabolomic profiling, and human genetics, we show that ATG7 deficiency shifts PT cell metabolism and differentiation toward growth at the expense of function. ATG7 loss impairs autophagy-mediated lipid droplet homeostasis, causing their accumulation and disrupting fatty acid transfer to mitochondria, compromising energy metabolism and cellular function. In zebrafish, reintroducing human wild-type ATG7 restores homeostasis, whereas inhibiting mitochondrial fatty acid oxidation induces phenotypic changes in wild-type cells. In humans, ATG7 variation associates with increased kidney disease risk, and loss-of-function variants cause tubular proteinuria and altered mitochondrial metabolism. Low ATG7 levels correlate with dedifferentiation, altered metabolic pathways, and poor renal cell carcinoma outcomes. Together, our results establish a metabolic paradigm that links autophagy to kidney epithelial cell fate specialization, with broad implications for health and disease.

A.U. and M.K. are affiliated with Insilico Medicine, a commercial company developing AI solutions for ageing research, drug discovery, and longevity medicine.

This study did not receive any funding

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human data were openly available before the initiation of the study in Gepia2 (http://gepia2.cancer-pku.cn/#general), Genebass ( https://app.genebass.org/), CIPHER (https://phenomics.va.ornl.gov/web/cipher/pheweb), in Human Genetic Evidence (HUGE) scores from the Common Metabolic Diseases Knowledge Portal (https://md.hugeamp.org/), in the UKbiobank (https://www.ukbiobank.ac.uk/), and in the Cancer Genome Atlas (https://www.cancer.gov/ccg/research/genome-sequencing/tcga).

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All data produced in the present study are available upon reasonable request to the authors.