Demethylzeylasteral inhibits osteosarcoma cell proliferation by regulating METTL17-mediated mitochondrial oxidative...

Osteosarcoma (OS) represents the most common primary bone malignancy, characterized by substantial disability and mortality, thereby underscoring the critical need for more effective therapeutic interventions to improve clinical outcomes. Demethylzeylasteral (DEM) is a bio-active compound has been reported for its anti-tumor properties through various mechanisms. Nonetheless, the specific effects of DEM on OS have yet to be fully elucidated. This study demonstrated that DEM significantly inhibited OS cell proliferation both in vitro and in vivo. Mechanistically, DEM impairs mitochondrial OXPHOS by targeting METTL17, a known regulator of mitochondrial translation, resulting in reduced ATP production. Subsequent investigations revealed that METTL17 knockdown exerts potent anti-tumor effects in OS, significantly suppressing both in vitro cell proliferation and in vivo xenograft tumor growth. Furthermore, METL17 overexpression significantly alleviated the inhibitory effects of DEM on cell proliferation, while restoring ATP production and oxygen consumption rates. These findings suggest that DEM impedes OS growth by inducing mitochondrial dysfunction through targeting METTL17, thereby highlighting a novel therapeutic strategy and potential molecular target for OS treatment.