E3 ligase LMO7 enhances temozolomide sensitivity by promoting MGMT degradation in lung cancer

Temozolomide (TMZ) is used to treat primary brain tumors and non-small cell lung cancer (NSCLC) brain metastases, yet therapeutic efficacy is often limited by the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT). Here, we identify the E3 ubiquitin ligase LIM domain only 7 (LMO7) as a regulator of TMZ sensitivity in NSCLC cells by promoting MGMT degradation. LMO7 directly binds MGMT via its F-box domain and promotes K48-linked polyubiquitination and proteasomal degradation of MGMT, thereby increasing TMZ sensitivity. TMZ treatment further strengthens the LMO7-MGMT interaction, creating a positive feedback loop that accelerates MGMT degradation and enhances TMZ sensitivity. Consistently, TMZ further strengthened the LMO7-MGMT interaction, and this enhancement was attenuated with the catalytically inactive MGMT-C145A mutant. In patient datasets, lower LMO7 expression and higher MGMT expression correlate with shorter overall survival in lung cancer (Kaplan-Meier Plotter analysis, p < 0.01). Together, these results indicate that LMO7-mediated MGMT degradation increases TMZ sensitivity in NSCLC, positioning LMO7 as a potential prognostic biomarker and therapeutic target.