Glycyrrhizin alleviates renal damage in MRL/lpr mice by modulating gut microbiota dysbiosis and regulating the RTK-PKCα axis: insights from reverse network pharmacology

The present investigation elucidates the therapeutic potential of glycyrrhizin, the predominant triterpene saponin isolated from Glycyrrhiza glabra (licorice), in the management of systemic lupus erythematosus (SLE), an autoimmune disorder characterized by multisystemic involvement and therapeutic recalcitrance. Comprehensive interrogation of multiple disease-specific databases facilitated the identification of crucial SLE-associated molecular targets and hub genes, with MAPK1, MAPK3, TP53, JUN, and JAK2 demonstrating the highest degree of network centrality. Subsequent molecular docking simulations and binding affinity assessments revealed compounds with exceptional complementarity to these pivotal molecular targets, establishing Glycyrrhiza glabra as a pharmacologically promising botanical source and glycyrrhizin as its principal bioactive constituent meriting comprehensive mechanistic investigation. Experimental validation employing the MRL/lpr murine lupus model demonstrated that glycyrrhizin treatment significantly diminished circulating autoantibody titers and markedly ameliorated the characteristic glomerulonephritis and tubular interstitial damage associated with lupus nephritis. Concomitant 16S rDNA gene sequencing-based microbiome profiling revealed that glycyrrhizin administration induced substantial modulation of the intestinal microbial ecosystem, specifically attenuating the abundance of Ruminococcus genus, a bacterial taxon previously implicated in the pathogenesis and exacerbation of lupus nephritis. Transcriptomic analysis utilizing Gene Expression Omnibus (GEO) repository datasets confirmed glycyrrhizin's profound regulatory effects on calcium signaling pathways. Mechanistically, glycyrrhizin suppresses renal receptor tyrosine kinase (RTK)-protein kinase C alpha (PKCα) axis activation, thereby interrupting key inflammatory and fibrotic signaling cascades. Collectively, these findings provide compelling evidence that glycyrrhizin confers nephroprotective effects in lupus nephritis through orchestrated dual mechanisms: (1) restoration of gut microbiota homeostasis, and (2) suppression of the renal RTK-PKCα signaling axis, thereby attenuating inflammatory cascades and preserving renal architectural integrity. These mechanistic insights advance our understanding of glycyrrhizin's therapeutic potential and establish a robust scientific foundation for its clinical translation in SLE management strategies.