Genomic and metabolomic insights into the enhancement of rare ginsenosides in Panax ginseng through solid-state fermentation by Aspergillus cristatus JH-5

The therapeutic efficacy of Panax ginseng is often restricted by the low bioavailability of its naturally abundant major ginsenosides. Biotransformation into deglycosylated rare ginsenosides, such as Rg3, significantly enhances pharmacological activity. This study evaluates the potential of Aspergillus cristatus JH-5, a fungus with a long history of safe use in food fermentation isolated from Fuzhuan brick tea, as a biocatalyst for ginseng fermentation. We employed a multi-omics strategy integrating whole-genome sequencing (WGS), untargeted metabolomics, and HPLC quantification to elucidate the metabolic changes and underlying genetic mechanisms. Fermentation induced a profound restructuring of the ginseng metabolome. Most notably, HPLC analysis revealed the de novo accumulation of rare ginsenosides Rg3(S) and Rg3(R) to a total content of 0.23% (dry weight), compounds undetectable in the unfermented control. Genomic analysis of the 28.29 Mb JH-5 genome identified a rich arsenal of Carbohydrate-Active enZymes (CAZymes), specifically pinpointing multiple β-glucosidase candidate genes (e.g., gene0147, gene2409) responsible for the targeted deglycosylation of major saponins. Furthermore, the genome lacked biosynthetic gene clusters for common mycotoxins, supporting the strain’s safety profile for food applications. These findings establish A. cristatus JH-5 as a safe and efficient agent for enriching high-value rare ginsenosides, providing a solid theoretical and genetic basis for the development of novel fermented ginseng products.