Zeaxanthin targets TOP2A to regulate autophagy and suppress lung cancer progression via the MAPK/ERK pathway

• Zeaxanthin suppresses lung cancer progression by inhibiting cell viability and migration. • TOP2A identified as a direct downstream target of zeaxanthin in lung cancer. • Zeaxanthin blocks MAPK/ERK signaling and increases autophagic flux. • TOP2A inhibition mediates autophagy activation and tumor suppression. • In vivo models confirm Zeaxanthin's efficacy in reducing tumor growth in lung cancer. Lung cancer (LC) remains a significant global health challenge, characterized by rapid progression and limited therapeutic options. Zeaxanthin (Zea), a natural carotenoid, exhibits promising antioxidant, anti-inflammatory, and anti-tumor activities; however, its precise mechanisms in LC are largely unexplored. Here, we demonstrate that Zea and DNA topoisomerase II A (TOP2A) significantly suppresses the viability, proliferation, and migration of LC cells while promoting apoptosis in vitro . Mechanistically, transcriptome analysis identified TOP2A as a critical downstream target. Molecular docking and cellular thermal shift assays further confirmed a direct interaction between Zea and TOP2A, suggesting Zea enhances TOP2A protein stability. We found that Zea inhibits TOP2A expression, which subsequently disrupts MAPK/ERK signaling and enhances autophagic activity, evidenced by increased autophagosome and autolysosome formation. Western blot and immunofluorescence analyses corroborated the modulation of key autophagy-related proteins. In vivo studies using an orthotopic LC model revealed that Zea treatment markedly reduced tumor growth, accompanied by decreased TOP2A and Ki67 expression. Collectively, our findings establish Zea as a potent LC therapeutic agent that suppresses tumor progression by targeting TOP2A, inhibiting the MAPK/ERK pathway, and ultimately modulating autophagy.