Targeting EGFR signaling: Crotonoside as a multi-mechanistic agent against non-small cell lung cancer.

[BACKGROUND] Non-small cell lung cancer (NSCLC), the predominant histological subtype of lung cancer, continues to pose a significant global health challenge due to its elevated incidence and mortality. Traditional Chinese medicine (TCM) has garnered growing recognition for its therapeutic potential in oncology. Croton tiglium L., a classical TCM herb, contains bioactive alkaloids with established anti-tumor properties. Although crotonoside-containing formulations exhibit anticancer efficacy in vivo, the molecular mechanisms underlying its effects on NSCLC are not fully understood.

[OBJECTIVE] This study aims to delineate the molecular mechanism through which crotonoside exerts therapeutic effects against NSCLC, with particular emphasis on EGFR signaling pathway modulation and associated downstream cascades.

[METHODS] This study used a multidisciplinary technical system to investigate the mechanism of crotonoside on NSCLC. First, the cytotoxicity of crotonoside on tumor cells was determined through in vitro cell experiments, and its impact on the apoptosis and migration of NSCLC cells was evaluated. Then, a subcutaneous xenograft mouse model was established to verify the anti-tumor effect of crotonoside in vivo. Network pharmacology and transcriptome analysis were applied to explore potential molecular targets. Differential gene expression and pathway enrichment were validated through qRT-PCR, Western Blotting, and immunohistochemistry.

[RESULTS] Crotonoside significantly inhibited the proliferation, migration, and angiogenesis of NSCLC cells. Mechanistically, it suppressed EGFR activation and attenuated downstream PI3K/Akt and MAPK/ERK signaling pathways, resulting in decreased expression of oncogenic mediators.

[CONCLUSION] Crotonoside exerts potent anti-NSCLC activity associated with modulation of the EGFR signaling pathway. These findings suggest that crotonoside may serve as a promising lead compound for further structural optimization and development of novel EGFR-targeted or multi-targeted therapeutics against NSCLC.