Daucosterol Inhibits Glycolysis and Malignant Progression of Lung Adenocarcinoma by Targeting ERBB2‐mediated PI3K/AKT Pathway Based on Network Pharmacology

Lung adenocarcinoma (LUAD) is the predominant subtype of non-small cell lung cancer (NSCLC) with high mortality and treatment resistance. While the natural compound daucosterol (DS) shows anti-tumor potential, its role and mechanism in LUAD are unclear. Network pharmacology identified potential DS targets in LUAD, with binding affinity confirmed by molecular docking and dynamics simulations. In vitro, cell counting kit 8 (CCK-8), flow cytometry, and transwell assays were used to assess LUAD cell proliferation, apoptosis, migration, and invasion. Western blot and glycometabolism assays were employed to measure protein expression and glycolysis (glucose consumption and lactate production). In vivo anti-tumor efficacy of DS was validated in a xenograft mouse model using immunohistochemistry (IHC) and western blot. DS dose-dependently inhibited LUAD cell viability, migration, and invasion while inducing apoptosis. Network pharmacology identified Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a key target for DS, supported by strong DS-ERBB2 binding affinity and complex stability. ERBB2 overexpression reversed DS-induced suppression of malignant phenotypes. Mechanistically, DS reduced ERBB2 expression to inhibit phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, down-regulating hexokinase 2 (HK2) and lactate dehydrogenase (LDHA), and reducing glucose consumption and lactate production. In vivo, DS inhibited xenograft tumor growth and decreased Ki67, ERBB2, p-PI3K/PI3K, p-AKT/AKT, HK2, and LDHA expression in tumor tissues, which were reversible upon ERBB2 overexpression. DS exerts anti-tumor effects in LUAD by directly regulating ERBB2 expression, inhibiting PI3K/AKT signaling, and disrupting glycolysis. These findings support DS as a promising therapeutic candidate for LUAD.