biostudies-literatureFan JNatural Science Foundation of Liaoning Province (Liaoning Provincial Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)820https://www.ebi.ac.uk/biostudies/studies/S-EPMC12602706biostudies-literatureUnknown16(1)Oral squamous cell carcinoma (OSCC) is an aggressive cancer with limited improvement in patient outcomes despite advances in surgery, chemotherapy, and radiotherapy. The LIM-only protein LMO4 functions as a transcriptional co-regulator and is known to be increased in several epithelial cancers, but its contribution to OSCC has not been well defined. In this study, we found that LMO4 expression was markedly higher in OSCC tissues and was associated with poorer overall survival. Cellular experiments showed that LMO4 enhanced OSCC cell proliferation, migration, and resistance to ferroptosis by promoting the ubiquitin-proteasome-dependent degradation of the tumor suppressor RAB17. Restoration of RAB17 expression reduced these malignant behaviors. In a nude mouse xenograft model, tumors with hiCell death & diseaseLMO4 promotes OSCC progression by inducing RAB17 degradation and ferroptosis resistance.PMC1260270620180530037821036492023JH2/20200093819027012022-MS-1832023JH2/20200036Liu LLiu MWang CZhang HXiang SDai WMa WLi YWang QFan JHuang ZJia SZhao FXu ZfalseLMO4 promotes OSCC progression by inducing RAB17 degradation and ferroptosis resistance.Oral squamous cell carcinoma (OSCC) is an aggressive cancer with limited improvement in patient outcomes despite advances in surgery, chemotherapy, and radiotherapy. The LIM-only protein LMO4 functions as a transcriptional co-regulator and is known to be increased in several epithelial cancers, but its contribution to OSCC has not been well defined. In this study, we found that LMO4 expression was markedly higher in OSCC tissues and was associated with poorer overall survival. Cellular experiments showed that LMO4 enhanced OSCC cell proliferation, migration, and resistance to ferroptosis by promoting the ubiquitin-proteasome-dependent degradation of the tumor suppressor RAB17. Restoration of RAB17 expression reduced these malignant behaviors. In a nude mouse xenograft model, tumors with hi2025-01-01T00:00:00Z2025 Nov2026-06-05T15:16:40.387Z2026-05-18T03:13:06.327ZS-EPMC126027064121390810.1038/s41419-025-08171-1