Flos Puerariae-Semen Hoveniae herb pair ameliorates acute alcohol-induced liver injury by dual-modulating IL-11-driven inflammation and restoring lipid homeostasis via the PI3K/AKT/mTO pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The flowers of Pueraria Lobata (Willd.) Ohwi and Semen Hoveniae (FS) herb pair is a classic Traditional Chinese Medicine (TCM) formulation long utilized for alleviating alcohol intoxication, relieving hangovers, and protecting the liver. Although it has been widely applied in clinical practice to treat alcoholic liver disease (ALD), the mechanisms underlying its multi-target efficacy, particularly its active absorbed constituents and their impact on lipid metabolism and inflammatory pathways, warrant further investigation.

AIM OF THE STUDY: To elucidate the active material basis and multi-target mechanisms of FS herb pair against acute alcohol-induced liver injury (AALI) by integrating serum pharmacochemistry, network pharmacology, lipidomics, and in vivo experimental validation.

MATERIALS AND METHODS: Bioactive components absorbed in rat serum following oral administration were identified using HPLC-FT-ICR MS. Potential therapeutic targets were computationally predicted and their possible binding interactions were assessed via molecular docking. In vivo, a mouse model of AALI was established and treated with the FS herb pair. Hepatoprotective effects were evaluated through histopathology, biochemical assays, oxidative stress indicators, and inflammatory cytokine profiling. Serum lipid profiles were analyzed using UPLC-QE-Orbitrap-MS-based lipidomics, and key signaling proteins (PI3K, AKT, mTOR, CYP2E1) and IL-11 expression were assessed by Western blotting and immunofluorescence.

RESULTS: A total of 20 F S herb pair-derived prototype components were identified in rat serum. Integrated analysis prioritized potential interactions between these constituents and targets such as AKT1, TNF, and EGFR, which were supported by favorable computationally predicted docking scores. In vivo validation demonstrated that FS herb pair significantly ameliorated alcohol-induced hepatic histopathological damage, reduced ALT, AST, and lipid accumulation (TC, TG). Mechanistically, FS herb pair suppressed CYP2E1-mediated oxidative stress (ROS, MDA) and downregulated the pro-inflammatory IL-11 signaling axis. Lipidomic analysis identified 44 lipid biomarkers, revealing that FS herb pair restored glycerophospholipid and fatty acid metabolism homeostasis. Alcohol exposure suppressed PI3K/AKT/mTOR signaling, and FS herb pair treatment partially restored this pathway. The observation that LY294002 attenuated the protective effects of FS herb pair provides pharmacological evidence consistent with a role for PI3K/AKT/mTOR activation in FS-mediated hepatoprotection.

CONCLUSION: The traditional FS herb pair alleviates AALI through a multi-dimensional mechanism. It dually mitigates CYP2E1/ROS-driven oxidative stress and IL-11-mediated inflammation, while restoring lipid homeostasis associated with the activation of the PI3K/AKT/mTOR pathway. This study provides supporting preclinical evidence for the traditional use of FS herb pair in AALI management.