Energy-sensing molecule RORγ regulates cholesterol metabolism and immune signaling in diabetic kidney disease and aging

Aging is a major risk factor for diabetic kidney disease (DKD), with both conditions exhibiting similar renal pathology. We identify the energy-sensing molecule Retinoic acid-related orphan receptor γ (RORγ) as significantly downregulated in diabetic and aged kidneys. Tubule-specific RORγ deficiency exacerbates kidney injury, whereas its overexpression protects. Mechanistically, RORγ stabilizes insulin-induced gene 1 (INSIG1) by upregulating the deubiquitinase YOD1 and enhancing AMPK activity via CAB39, which together promote INSIG1 phosphorylation and subsequent stabilization. Stabilized INSIG1 potently blocks the ER-to-Golgi transport and activation of SREBP2 (cholesterol synthesis) and STING (inflammatory signaling). In diabetes, RORγ itself is suppressed transcriptionally by CTCF and functionally by impaired AMPK/SIRT1 signaling, which hinders its activation. Importantly, administration of a RORγ agonist or RORγ-enriched exosomes effectively alleviates diabetic kidney injury. Thus, RORγ emerges as a key regulatory node that mitigates DKD and renal aging by co-regulating AMPK-mediated metabolic and STING-driven innate immune pathways through INSIG1 stabilization. Aging boosts diabetic kidney disease risk via shared renal pathology. Renal RORγ is downregulated in diabetes/aging; its tubule-specific loss worsens injury, and overexpression protects. RORγ stabilizes INSIG1 via YOD1/CAB39, blocking SREBP2/STING.