Function of molecular-weight-optimized Astragalus polysaccharides in cisplatin-caused acute kidney injury: mechanisms centered on gut microbiota regulation and precise treatment approaches.

Abstract

Cisplatin is a widely used chemotherapeutic drug for solid tumors, including colorectal cancer, but its clinical application is limited by dose-dependent nephrotoxicity, often resulting in acute kidney injury (AKI). The gut-kidney axis has emerged as a key factor in cisplatin-induced AKI, with gut microbial imbalance contributing to inflammation and metabolic dysregulation. Astragalus polysaccharides (APS), the main bioactive constituents of Astragalus membranaceus , have shown potential in mitigating AKI, partly through modulation of the gut microbiota. Clinical sequencing data indicate that cisplatin treatment reduces short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium, Roseburia ) and increases potentially pathogenic groups (e.g., Enterobacteriaceae ), leading to alterations in SCFA, amino acid, and bile acid metabolism. This study integrates these findings with existing literature to propose a molecular-weight (Mw)-defined APS model targeting the gut-kidney axis. While high-Mw APS (>100 kDa) primarily act via microbial fermentation to restore SCFA production and gut barrier function, low-Mw APS (< 10 kDa) may exert direct anti-inflammatory and anti-apoptotic effects. Advanced gut-targeted delivery systems are also discussed as strategies to enhance APS bioavailability and colonic targeting. Understanding these Mw-dependent mechanisms is critical for developing APS as a precise adjunct therapy to prevent cisplatin-induced AKI and improve patient outcomes.