ABSTRACT Non‐alcoholic fatty liver disease (NAFLD) is a common metabolic liver disorder with limited effective pharmacological treatments. Tetrandrine (Tet), a major bioactive alkaloid derived from Stephaniae Tetrandrae Radix , has shown anti‐inflammatory and metabolic regulatory potential. In this study, we systematically investigated the therapeutic effects and underlying mechanisms of STR alkaloids, with a focus on Tet in NAFLD. Network pharmacology identified active alkaloids and 194 overlapping targets associated with NAFLD, and protein–protein interaction analysis highlighted TP53, EGFR, STAT3, AKT1, and TNF as key hub genes. Functional enrichment analyses indicated that the PI3K/AKT, MAPK, and FoxO signaling pathways were significantly involved, with PI3K/AKT emerging as the central signaling pathway. Molecular docking and molecular dynamics simulations demonstrated stable binding interactions between Tet and STAT3 as well as TNF. Mendelian randomization analysis further suggested a causal relationship between elevated STAT3 expression and increased NAFLD risk. Experimental validation in a thioacetamide‐induced zebrafish NAFLD model showed that Tet significantly reduced hepatic lipid accumulation and decreased serum TG, TC, ALT, and AST levels. Mechanistically, Tet activated PI3K/AKT/STAT3 signaling while inhibiting TP53 and Bax. External validation using GEO datasets supported AKT1 and EGFR as important regulatory genes. Overall, these findings demonstrated that Tet ameliorates NAFLD by modulating lipid metabolism and apoptosis through activation of the PI3K/AKT/STAT3 signaling pathway, providing integrated computational, genetic, and experimental evidence for its potential as a therapeutic agent.
Sun et al. (2026) studied this question.