Cassiaside C alleviates IRI-induced AKI through restoring the expression of ATGL to reduce lipid droplet accumulation.

Acute kidney injury (AKI) is a prevalent and severe clinical condition. The most common etiology of AKI is renal ischemia/reperfusion injury (IRI), which is closely linked to dysregulation of lipid homeostasis and abnormal accumulation of lipid droplets (LDs) in renal tubular epithelial cells (RTECs) following ischemic insult. Cassiaside C is a naturally occurring naphthoquinone compound isolated from the seeds of Cassia obtusifolia, a traditional Chinese medicinal herb. While Cassia seeds have demonstrated pharmacological activity against various inflammatory conditions, the role of Cassiaside C in regulating lipid homeostasis and promoting lipid droplet degradation in RTECs during AKI remains unclear. This study aims to investigate the protective effects of Cassiaside C against renal ischemia-reperfusion injury and to elucidate the underlying molecular mechanisms. The therapeutic potential of Cassiaside C was evaluated by treatment in the hypoxia/reoxygenation (H/R) model of the HK-2 cell line and the renal ischemia-reperfusion (IR) model in mice. Our results show that Cassiaside C significantly attenuated lipid deposition in renal tubular epithelial cells during IRI-AKI, concomitantly reduced the expression of renal injury biomarkers, and improved overall renal function. Mechanistically, molecular docking and Western blot analyses indicated that Cassiaside C may directly bind to adipose triglyceride lipase (ATGL) and inhibit ATGL degradation, thereby enhancing lipid degradation. These findings suggest that Cassiaside C is a promising candidate for the treatment of IRI and may represent a novel therapeutic strategy targeting lipid metabolic dysfunction in AKI.