Ginsenoside Rb1 mitigates senescence-associated hepatic steatosis in mice through enhanced lysine degradation

The liver is the central organ for metabolism and detoxification, and its function gradually declines with age, often accompanied by pathological changes such as lipid metabolism disorders, inflammatory responses, and fibrosis, significantly increasing the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Ginsenoside Rb1 (Rb1) is a major active constituent of ginseng. However, its regulatory mechanism on hepatic lipid metabolism and MASLD/MASH-related phenotypes during natural aging remains unclear.

To explore the effects of Rb1 on liver aging phenotypes, lipid deposition, inflammation, fibrosis, and related metabolic pathways in naturally aged mice, and to further elucidate the underlying regulatory mechanisms.

Naturally aged male C57BL/6J mice (72-week-old) were used and divided into the Old group and the Rb1 treatment group (Old + Rb1). Young mice (6-week-old) served as controls. Therapeutic effects were evaluated through histopathology (H&E, Masson trichrome, Oil Red O staining), immunofluorescence (p21, FASN, FABP1, PPARα), immunohistochemistry (PCNA, F4/80), RT-qPCR analysis of lipid metabolism-related genes. Additionally, untargeted metabolomics analyses of both serum and liver tissues, as well as liver transcriptome sequencing, were performed to investigate the underlying mechanisms.

Rb1 alleviated hepatocellular senescence, as evidenced by reduced p21 expression and increased PCNA-positive cells. It ameliorated age-related hepatic pathological damage, as evidenced by reduced inflammatory infiltration (F4/80) and collagen deposition (Masson staining), along with improved hepatocellular vacuolation and lipid accumulation (Oil Red O staining). Rb1 regulated hepatic lipid metabolism through three mechanisms: inhibiting lipid synthesis (Fasn, Acaca, Srebf1), modulating lipid transport (Fabp1, Slc27a2), and promoting lipid oxidation (Pparα, Fgf21). Serum and hepatic metabolomics consistently revealed that Rb1 activated the lysine degradation pathway, accompanied by an increase in the key intermediate metabolite trimethyllysine (TML). Liver transcriptome sequencing further indicated an increasing trend in the numbers of genes associated with the biological process of metabolic process and the molecular functions of transporter activity and transcription regulator activity. Additionally, enrichment of the biological process of lipid export from the cell was observed in the comparison between the Old and Old+Rb1 groups.

Rb1 ameliorates age-related hepatic lipid accumulation and pathological damage in naturally aged mice by promoting the lysine degradation pathway and comprehensively remodeling lipid metabolic homeostasis. These findings provide a potential target and theoretical basis for intervention in aging-related MASLD/MASH.