Abietic Acid Induces DNA Damage and Cell Apoptosis in Lung Cancer Cells Through Targeting TOP2A

<b>Background</b>: This study investigated the therapeutic effects and underlying mechanisms of abietic acid, an abietane diterpene extracted from <i>Pimenta racemosa</i> var. <i>grissea</i>, against lung cancer. <b>Methods</b>: Initially, cell viability, colony formation, flow cytometry, and mitochondrial membrane potential detection were conducted to determine the impact of abietic acid on lung cancer cells. Subsequently, the antitumor mechanisms of abietic acid were predicted using network pharmacology and validated via immunofluorescence, reactive oxygen species (ROS) detection, molecular docking, gene knockdown techniques and Western blotting. Finally, an in vivo xenograft model assessed its tumor-suppressive potential, with Hematoxylin-Eosin (H&E) staining, Western blotting, and immunohistochemistry performed to examine pathological changes and protein expression alterations. <b>Results</b>: The proliferation of lung cancer cells was significantly inhibited by abietic acid. Additionally, abietic acid induced apoptosis and reduced mitochondrial membrane potential. Network pharmacology and Gene Ontology (GO) enrichment analysis revealed that the DNA damage response was a key biological process affected by abietic acid. Further results demonstrated that abietic acid induces DNA damage in lung cancer cells through targeting DNA topoisomerase II alpha (TOP2A). In vivo studies confirmed the antitumor efficacy of abietic acid and its low systemic toxicity. <b>Conclusions</b>: Abietic acid demonstrated significant antitumor effects in lung cancer cells by downregulating TOP2A, which induced DNA damage and apoptosis, revealing its clinical potential.