Crocins ameliorate acute kidney injury in glycerol-induced rhabdomyolysis by targeting the PLIN1/PPARs signaling pathway.

BACKGROUND: Rhabdomyolysis (RM) is a potentially life-threatening syndrome characterized by skeletal muscle damage, with acute kidney injury (AKI) being its most severe complication. Currently, no effective treatment exists for RM-induced AKI. Crocins, the major bioactive constituents extracted from the stigma of Crocus sativus L. (Saffron), possess diverse pharmacological activities. OBJECTIVES: This study aimed to explore the pharmacological effect and possible mechanism of crocins in the treatment of RM-induced AKI. METHOD: Network analysis was first applied to predict potential targets of crocins against RM. A rat model of hypertonic glycerol-induced RM was then established to evaluate pharmacological effect, including assessment of muscle and renal pathology, inflammatory cytokines, biochemical markers, and oxidative stress-related enzymes. Tandem mass tag-based quantitative proteomics was further employed to identify key disease targets. Molecular docking was then conducted to validate potential target interactions of crocins in RM-induced AKI treatment. RESULTS: Animal experiments demonstrated that crocins alleviated muscle and renal injuries by inhibiting inflammation and oxidative stress while preserving hepatic and renal functions. Proteomic analysis identified perilipin 1 (PLIN1) as a critical candidate biomarker mediating these effects. Both network analysis and proteomics indicated that the peroxisome proliferator-activated receptors (PPARs) signaling pathway was closely involved in protective mechanism. Furthermore, Western blotting confirmed that crocins exerted pharmacological effect through regulating the PLIN1/PPARs signaling pathway. Molecular docking revealed that the best docking activities were demonstrated by crocin I/II-PLIN1, crocin I-PPARα, and crocin II-PPARγ. CONCLUSION: Crocins mitigated RM-induced AKI primarily by suppressing inflammation and oxidative stress via the PLIN1/PPARs signaling pathway. These findings provide a scientific and theoretical basis for the potential clinical application of crocins in treating RM-induced AKI.