Targeting KIF11 degradation: Oxypeucedanin inhibits lung adenocarcinoma progression by disrupting the MCM2-CDK1 signaling pathway.

Background

AND

Purpose

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Current targeted therapies are limited by acquired resistance, highlighting the urgent need for novel therapeutic agents and targets. The aim of this study is to investigate the anti-tumor efficacy of oxypeucedanin (OPD) against LUAD and elucidate its underlying molecular mechanism. EXPERIMENTAL APPROACH In vitro functional assays, bioinformatics prediction, molecular docking, and binding validation experiments were employed to identify the direct target of OPD. Ubiquitination assays, co-immunoprecipitation coupled with mass spectrometry, and proteomic analysis were used to delineate the downstream pathway. Genetic knockdown/ overexpression rescue experiments were performed, and in vivo efficacy was evaluated using patient-derived organoids and mouse xenograft models.

Results

OPD potently suppressed LUAD cell proliferation and induced apoptosis both in vitro and in vivo. Mechanistically, OPD directly bound to the motor protein KIF11 and promoted its ubiquitin-proteasomal degradation via the E3 ligase TRIM21. KIF11 degradation led to destabilization of its interacting partner, MCM2, consequently downregulating the CDK1/ Cyclin B1 complex and ultimately triggering G2/M phase cell cycle arrest.

Conclusion

AND IMPLICATIONS OPD functions as a novel molecular degrader of KIF11, exerting its anti-LUAD effects by promoting KIF11 ubiquitination and subsequent proteasomal degradation. These results highlight OPD as a promising therapeutic strategy for LUAD.