Targeting the HIF-1α/PPARγ axis with curcumin carbon dots to combat uranium nephrotoxicity

Uranium-induced nephrotoxicity involves complex mechanisms and lacks therapeutic interventions. This study identifies the HIF-1α/PPARγ axis as a key driver of renal lipid reprogramming and injury following uranium exposure. Using molecular docking, co-immunoprecipitation (Co-IP), ChIP-qPCR, and dual-luciferase reporter assays, we confirmed that HIF-1α directly regulates PPARγ expression and downstream lipotoxicity. The causal role of this axis was further validated using HIF-1α knockdown/knockout models and PPARγ pharmacological modulators (GW9662 and Rosi). Curcumin-derived carbon dots (CCDs) were synthesized at temperatures ranging from 120 to 210 °C. As-prepared CCDs-210 exhibited uniform size (< 10 nm), and excellent biocompatibility. Carbonization temperature governed cellular uptake: CCDs-210 entered via active endocytosis, while CCDs-120 used passive diffusion. In uranium-exposed HK-2 cells, CCDs-210 scavenged ROS, stabilized mitochondrial membrane potential, and suppressed the HIF-1α/PPARγ axis, reversing lipid dysregulation and improving cell viability. In vivo, CCDs-210 attenuated renal histopathological damage, restored renal function, and conferred multi-organ protection. These findings establish the HIF-1α/PPARγ axis as a central mediator of uranium nephrotoxicity and demonstrate that CCDs-210, by targeting this axis, effectively mitigate oxidative stress, inflammation, and lipid metabolic disruption. This work provides both a mechanistic foundation and a translatable nanotherapeutic strategy for treating uranium-induced kidney injury.