Kinsenoside

Hyperuricemia (HUA) involves multi-organ dysfunction, particularly hepatic and renal abnormalities. Danggui-Niantong decoction (DGN) is a traditional formula for gout and chronic kidney disease. Clinically, DGN is often combined with drugs that regulate hepatic function to treat HUA. Anoectochilus roxburghii (AR) is recognized for its hepatoprotective properties. However, whether the AR and DGN combination (AR+DGN) exerts superior urate-lowering and organ-protective effects compared to monotherapy, and the mechanisms underlying this combined treatment, remain unclear.

This study aimed to evaluate the therapeutic efficacy of AR, DGN, and AR+DGN in hyperuricemic rats, and to investigate the mechanisms of this combined action via integrated gut microbiota and metabolomics analyses.

First, the active components and fingerprints of AR and DGN were characterized using UPLC-MS and HPLC. A hyperuricemic model was established in male Sprague-Dawley rats via a high-purine diet. Following a preliminary experiment to determine the optimal AR dose (n = 30), 48 rats were randomized into six groups (n = 8): Control, HUA, Benzbromarone (Ben), AR, DGN, and AR+DGN. After 4 weeks of intragastric administration, therapeutic efficacy was assessed via serum uric acid (SUA), hepatorenal function markers, and histopathology. Subsequently, 16S rRNA sequencing and untargeted metabolomics were employed to screen potential signaling pathways, which were further validated by western blot, immunofluorescence, and RT-qPCR.

A total of 296 compounds were identified collectively across the AR and DGN extracts, and ten bioactive markers, including kinsenoside, chlorogenic acid, and isoimperatorin, were rigorously quantified for quality standardization. Compared to monotherapy, AR+DGN provided dual protection by restoring both hepatic and renal functions and demonstrated a superior urate-lowering capacity, reducing SUA levels by 58.2% and serum alanine aminotransferase levels by 59.6% compared to the HUA group (p < 0.01), while maintaining normal liver enzyme levels unlike benzbromarone. Mechanistically, AR+DGN restored gut microbiota dysbiosis in hyperuricemic rats, notably enriching seven beneficial genera (e.g., Alistipes and Bifidobacterium) while depleting four pathogenic genera (e.g., Escherichia-Shigella and Coriobacteriaceae_UCG_002). Furthermore, elevated levels of beta-nicotinamide mononucleotide, propionate, butyrate, and isobutyrate, along with reduced inosine and xanthine, were identified as key metabolites significantly associated with these microbial alterations (p < 0.05). KEGG analysis identified NAD⁺ metabolism and purine metabolism as key pathways co-regulated in both serum and intestinal contents. Critically, AR+DGN upregulated hepatic NAD⁺ biosynthetic enzymes (QPRT, NMNAT3, and NAMPT by 1.74-, 2.64-, and 1.79-fold, respectively), thereby boosting liver and serum NAD⁺ levels. This metabolic restoration, coupled with a 62.5% reduction in hepatic reactive oxygen species, indicated the disruption of the uric acid-oxidative stress positive feedback loop. Simultaneously, AR+DGN restored renal urate transport balance by inhibiting reabsorptive transporters (GLUT9, URAT1) while upregulating the secretory transporter (ABCG2), ultimately contributing to the significant urate-lowering efficacy.

This study demonstrates that AR+DGN exerts superior urate-lowering efficacy and hepatorenal protection. Mechanistically, it functions by remodeling the gut microbiota-metabolic axis to regulate hepatic NAD⁺ metabolism and renal urate transport, supporting its potential for the safe and long-term management of HUA.

Lean metabolic dysfunction - associated steatotic liver disease (MASLD) occurs in individuals with normal BMI and is linked to progressive liver injury, fibrosis, hepatocellular carcinoma, and adverse metabolic outcomes. Its distinct clinical and biological features underscore the need for tailored diagnostic and therapeutic strategies.

Herein, the authors review the dietary, genetic, and bile acid - focused animal models that recapitulate lean MASLD mechanisms. Literature was identified in PubMed and Scopus (January 2000-June 2025) using the terms lean MASLD, non-obese MASLD, MASH, and animal models, with reference lists screened for additional studies. Utilization of Methionine - choline-deficient (MCD) and choline-deficient (CD) diets can help reveal mechanisms pertinent to oxidative stress, macrophage activation, and fibrogenesis, whereas cholesterol- and bile acid - enriched diets more closely reproduce the steatohepatitis and fibrosis observed in lean human contexts. Genetic models (e.g. Pemt^-/^-, cGas^-/^-) reveal roles for autophagy, microbial DNA sensing, and metabolic rewiring. These platforms have been used to test candidate therapies, including GLP-1 analogues (exendin-4, liraglutide), kinsenoside, silibinin, and bile-acid modulators, and to interrogate gut - liver axis disruption that supports microbiota-targeted strategies.

Lean MASLD is mechanistically distinct from obesity-related MASLD. Animal models have advanced our understanding of their unique drivers, including bile acid dysregulation, leptin signaling, and oxidative stress. These insights may guide the development of targeted therapies tailored to lean patients and improve clinical outcomes through individualized approaches.