Tubular Cell Senescence Disrupts FOXO1-Dependent Renal Gluconeogenesis During Starvation in Chronic Kidney Disease

Renal gluconeogenesis accounts for a substantial fraction of systemic glucose production during starvation, yet its regulation and pathological disruption in chronic kidney disease (CKD) remain poorly understood. Here, we investigated the mechanisms governing renal gluconeogenesis during starvation and their impairment in CKD. Integrated transcriptome analysis of starved mouse kidneys revealed that starvation robustly induces gluconeogenic gene expression in proximal tubular epithelial cells through activation of FOXO1. Consistently, tubule-specific deletion of FOXO1 (FOXO1^flox/flox^; Ksp-Cre) markedly reduced renal gluconeogenic enzyme expression and resulted in hypoglycemia during starvation, establishing FOXO1 as a critical regulator of renal glucose production. In multiple CKD models, basal serum glucose levels were preserved despite suppressed renal FOXO1 activation and gluconeogenic gene expression, indicating compensatory glucose production under fed conditions. In contrast, during prolonged starvation, CKD mice developed profound hypoglycemia accompanied by impaired FOXO1 activation and insufficient induction of renal gluconeogenesis, a phenotype that was similarly observed in aged mice. In human CKD kidneys, a senescent tubular cell state was associated with coordinated downregulation of gluconeogenesis-related genes. These findings were recapitulated in cisplatin-induced senescence models, which showed diminished FOXO1 activity, reduced gluconeogenic gene expression, and decreased glucose production. Collectively, these findings identify tubular cell senescence as a pathogenic mechanism that disrupts FOXO1-dependent renal gluconeogenesis, thereby compromising glucose homeostasis during starvation in CKD and aging. Targeting tubular senescence or restoring FOXO1 signaling may represent therapeutic strategies to prevent starvation-induced hypoglycemia in these conditions.