FBXL5 depletion as a novel strategy against osteosarcoma: Evidence for MEK/ERK inhibition and enhanced therapeutic sensitivity.
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Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents. Despite standard treatments, including surgery and chemotherapy, the 5-year survival rate for metastatic OS remains <20%, underscoring the need for novel therapeutic targets. F-box and leucine-rich repeat protein 5 (FBXL5) is an E3 ubiquitin ligase that regulates iron homeostasis and exhibits complex functions across different tumors; however, its role in OS is still unclear. The present study employed the MG63 and 143B OS cell lines to investigate the oncogenic potential of FBXL5 through in vitro and in vivo experiments. Lentivirus-mediated FBXL5 knockdown significantly suppressed cell proliferation, migration and invasion, while promoting apoptosis. RNA sequencing analysis after FBXL5 silencing revealed significant alterations in the mitogen-activated protein kinase signaling pathway, particularly affecting the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) axis. Consequently, FBXL5 depletion reduced the expression and phosphorylation of Ras, Raf, MEK and ERK. In a mouse xenograft tumor model, FBXL5 knockdown inhibited tumor growth and reduced tumor volume. These findings suggest that FBXL5 promotes OS progression via regulation of the MEK/ERK signaling pathway, suggesting that it may be a useful therapeutic target and potential prognostic indicator; further validation in larger clinical cohorts is warranted.