Semen Sojae Praeparatum ameliorates triptolide-induced liver injury by regulating bile acid homeostasis and the Keap1/Nrf2/p62 axis.

BACKGROUND

Semen Sojae Praeparatum (SSP) exhibits both preventive and therapeutic effects against drug-induced liver injury (DILI). Traditionally, SSP is used in combination with Gardeniae fructus to prevent its hepatotoxicity. Isoflavones, the primary components of SSP, can mitigate DILI induced by chemotherapeutic agents such as acetaminophen and cisplatin. However, the potential of SSP to alleviate the hepatotoxicity of triptolide (TP, a prototypical compound in DILI research) remains unexplored.

PURPOSE: This study aimed to explore the protective effects and potential mechanisms of SSP on TP-induced liver injury.

METHODS

The phytochemical profile of the SSP extracts was characterized using UPLC-Q-TOF-MS. Hepatoprotective effects of SSP were assessed using a TP-induced liver injury mouse model. The mechanisms were predicted by metabolomic and proteomic analyses, and further elucidated by RT-qPCR, western blotting and transmission electron microscopy.

RESULTS

Isoflavones were identified as the main components of the SSP extracts. SSP treatment alleviated TP-induced abnormalities in serum biochemical markers, liver index and pathological damage. Multi-omics analysis revealed SSP modulated bile acid (BA) metabolism and autophagy, with Keap1 serving as a core protein. Furthermore, SSP reduced intrahepatic BA accumulation by enhancing hepatic BA transport rather than inhibiting BA synthesis. Additionally, SSP reversed TP-induced abnormalities in Keap1 and p62 expression and nuclear translon cation of the Nrf2 transcription factor, and mitigated oxidative imbalance and autophagic cell death.

CONCLUSIONS

SSP ameliorated TP-induced liver injury by modulating bile acid homeostasis and the Keap1/Nrf2/p62 pathway, thereby alleviating oxidative stress and excessive autophagy.