The potential of Kadsura longipedunculata against herb and chemical induced liver injury.

Kadsura longipedunculata is a Yi ethnic herb for hepatic disorders treatment in China. However, its effects on herb- and chemical-induced liver injury remain unknown. To validate traditional ethnomedicinal applications of K. longipedunculata and characterize its bioactive constituents. The hepatoprotective effect was evaluated using a triptolide-induced mice liver injury model. Bio-guided isolates were screened in an acetaminophen (APAP)-induced HepG2 cell model. Underlying signaling pathways were investigated using transcriptomics, network pharmacology, molecular docking, molecular dynamics simulations, and subsequent Western blotting validation. Abnormal biochemical indices, antioxidant defenses, and liver pathological necrosis in triptolide-induced mice were all adjusted by treatment with K. longipedunculata extract, exhibiting effects superior to those of the positive control, silymarin. The PI3K/AKT/NF-κB signaling pathway was identified as a core therapeutic pathway through transcriptomic profiling, supported by the upregulation of phosphorylated AKT and MTOR concurrent with the downregulation of NF-κB and TNF-α. Four compounds were isolated, among which catechin-5-O-β-D-glucopyranoside (Catechin GP) showed potent anti-apoptotic and antioxidative bioactivities in APAP-induced hepatocytes through the same pathway. The formation of a stable Catechin GP-AKT1 complex was further supported by computational analyses of binding stability and safety. The protective effect of K. longipedunculata and its bioactive compound, Catechin GP, against liver injury triggered by both herbal (triptolide) and chemical (acetaminophen) agents is regulated via the PI3K/AKT/NF-κB pathway.