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Aconitine from Aconiti Lateralis Radix Praeparata (Fuzi) Suppresses Intrahepatic Cholangiocarcinoma via TOP2A: A
Shuang-Nan Zhou1, Jing-Jing Zhang2, Da-Li Zhang2
1Senior Department of Infectious Disease, Chinese PLA General Hospital, Beijing, 100039, China.
Objective:
To elucidate the therapeutic potential and mechanisms of Fuzi (Aconiti Lateralis Radix Praeparata) against intrahepatic cholangiocarcinoma (ICC).
Methods:
Fuzi-related targets were obtained from TCMSP, HERB, and ETCM databases, and ICC-related differentially expressed genes were retrieved from Gene Expression Omnibus. Common hub targets were identified using network pharmacology and machine learning, followed by functional enrichment and immune infiltration analyses. Effects of aconitine, a major alkaloid of Fuzi, were validated in RBE cells using qPCR, Western blot, Transwell assays, and flow cytometry.
Results:
Thirty-six common genes were identified, mainly enriched in metabolic and cancer-related pathways. Topoisomerase II alpha (TOP2A) and alpha1A-adrenergic receptor (ADRA1A) were identified as hub genes with high diagnostic value (area under curve>0.98). High TOP2A expression was linked to poor disease-free survival. Several immune cells, including regulatory T cells, showed altered infiltration in ICC and correlated with hub gene expression. Aconitine inhibited the proliferation, migration, and invasion of RBE cells in a dose- and time-dependent manner (P<0.05 or P<0.01). It also induced G1 phase arrest and apoptosis, accompanied by modulation of Bcl-2 and Bax expression, and downregulation of TOP2A. TOP2A knockdown similarly reduced migration and invasion and altered Bcl-2/Bax expression, but had limited effects on apoptosis rate or cell cycle distribution.
Conclusion:
TOP2A was identified as Fuzi's potential therapeutic target in ICC, where its compound aconitine exerts antitumor effects by downregulating TOP2A, providing novel mechanistic insights and targeted therapy potential.
