LAUSR

Summary Glycyrrhiza uralensis Fisch is a medicinal plant widely used to treat multiple diseases in Europe and Asia, and its efficacy largely depends on liquiritin and glycyrrhizic acid. The regulatory pattern responsible for the difference in efficacy between wild and cultivated G. uralensis remains largely undetermined. Here, we collected roots and rhizosphere soils from wild (WT) G. uralensis as well as those farmed for 1 year (C1) and 3 years (C3), generated metabolite and transcript data for roots, microbiota data for rhizospheres and conducted comprehensive multi‐omics analyses. We updated gene structures for all 40 091 genes in G. uralensis, and based on 52 differentially expressed genes, we charted the route‐map of both liquiritin and glycyrrhizic acid biosynthesis, with genes BAS, CYP72A154 and CYP88D6 critical for glycyrrhizic acid biosynthesis being significantly expressed higher in wild G. uralensis than in cultivated G. uralensis. Additionally, multi‐omics network analysis identified that Lysobacter was strongly associated with CYP72A154, which was required for glycyrrhizic acid biosynthesis. Finally, we developed a holistic multi‐omics regulation model that confirmed the importance of rhizosphere microbial community structure in liquiritin accumulation. This study thoroughly decoded the key regulatory mechanisms of liquiritin and glycyrrhizic acid, and provided new insights into the interactions of the plant's key metabolites with its transcriptome, rhizosphere microbes and environment, which would guide future cultivation of G. uralensis.