4-Hydroxytamoxifen suppresses the malignant progression of lung adenocarcinoma by inhibiting MAPK signaling pathway

Lung adenocarcinoma (LUAD) has poor clinical outcomes due to limited therapeutic options and drug resistance. Here, 4-hydroxytamoxifen (4-OHT) was identified as a potential anti-tumor agent through drug repurposing screening of a human endogenous metabolite library. 4-OHT inhibited proliferation of A549 and PC9 cells, suppressed cell migration, reversed epithelial-mesenchymal transition (EMT), and induced apoptosis. Transcriptomic and metabolomic analyses revealed that 4-OHT downregulated fatty acid metabolism-related genes and inhibited the MAPK signaling pathway, leading to a significant reduction in intracellular lipid metabolites. Rescue experiments demonstrated that 4-OHT inhibited the phosphorylation of MEK/ERK, while MAPK activation reversed 4-OHT-induced lipid deficiency and growth inhibition. In vivo experiments further showed that 4-OHT significantly suppressed subcutaneous tumor growth in LUAD mouse models. Together, these findings suggest that 4-OHT exerts anti-tumor effects in part by inhibiting MAPK signaling-mediated lipid metabolism reprogramming, supporting its further evaluation as a repurposed agent for LUAD treatment.