Hexokinase 2 elevation links obesity to increased risk of acute kidney injury.

Acute kidney injury (AKI) is a common complication with poor clinical outcomes, and patients with high body mass index (BMI) are particularly vulnerable, especially after major surgical procedures, though the underlying mechanisms remain unclear. In this study, we used a Western diet (WD)-induced obesity model to examine how obesity influences Ischemia-reperfusion injury (IRI)-induced AKI and to explore the mechanisms involved. We found that obesity alone did not cause renal damage in healthy mice but markedly worsened kidney injury following IRI. RNA sequencing and bioinformatic analyses identified upregulation of hexokinase-2 as a key mediator of this effect. Notably, pharmacologic inhibition of hexokinase-2 restored metabolic balance in cultured human proximal tubule epithelial cells and alleviated renal injury in obese mice with AKI. Furthermore, clinical data showed that higher BMI and increased hexokinase-2 expression were associated with more severe tubular injury in patients with acute tubular necrosis. These findings demonstrate that obesity aggravates AKI through hexokinase-2-mediated metabolic reprogramming and suggest that targeting hexokinase-2 could be a promising therapeutic strategy for obese individuals at risk of AKI.