Cepharanthine suppresses lung adenocarcinoma through targeting glutathione peroxidase 4

Lung cancer poses a marked threat to global health, with lung adenocarcinoma (LUAD) being a predominant subtype. Despite their availability, treatment options often fall short of expectations. In this context, Traditional Chinese Medicine, known for its multifaceted therapeutic effects and favorable safety profile, has emerged as a promising alternative. In particular, cepharanthine (CEP), a bisbenzylisoquinoline alkaloid derived from <i>Stephania cepharantha</i>, has demonstrated the ability to suppress the proliferation of a range of tumor cells. However, the precise mechanisms by which CEP impacts LUAD remain to be elucidated. The present study focused on the anti-tumor effects of CEP on LUAD. Cellular experiment analysis revealed that CEP exhibited an IC₅₀ value of 6.810 µM for the H1299 cell line and 9.041 µM for the PC-9 cell line, with minimal toxicity to normal BEAS-2B cells. Bioinformatics analysis identified three potential target genes for CEP, namely glutathione peroxidase 4 (GPX4), tyrosyl-DNA phosphodiesterase 1 and carbonic anhydrase 4, among which CEP significantly suppressed the expression of GPX4 in LUAD cells. Further validation showed that the impact of CEP on cell proliferation, apoptosis and invasiveness was diminished in cells with GPX4 knockdown. <i>In vivo</i> experiments demonstrated that CEP could inhibit the growth of subcutaneously transplanted tumors in mice, however its therapeutic effect was reduced in GPX4 gene knockout mice bearing GPX4-knockdown tumors. In summary, CEP may exert its anti-LUAD effects by targeting GPX4, thereby offering a novel therapeutic strategy for LUAD treatment.