Epitranscriptomic silencing of STK25 promotes ferroptosis evasion via the METTL3-YAP-GPX4 axis in osteosarcoma.

Abstract

Osteosarcoma (OS) is an aggressive bone malignancy with poor outcomes in recurrent and metastatic disease. Although ferroptosis represents as a promising therapeutic strategy, its regulation in OS remains incompletely understood. Here, we identified STK25 as a regulator of ferroptosis susceptibility and tumor growth in OS. Transcriptomic analysis of paired parental and multidrug-resistant OS cell lines identified lower STK25 expression in the resistant derivatives. In a retrospective tissue microarray, low tumor STK25 expression was associated with a lower histological tumor necrosis rate after neoadjuvant chemotherapy and shorter survival. Mechanistically, METTL3 overexpression reduced STK25 reporter activity and accelerated STK25 mRNA decay in an m6A-site-dependent manner. STK25 depletion was accompanied by reduced Hippo pathway activity, increased YAP nuclear localization, and increased GPX4 expression, whereas STK25 restoration increased LATS1 and YAP phosphorylation, reduced GPX4 expression and sensitized OS cells to ferroptosis. GPX4 re-expression partially rescued cell viability and oxidative-stress phenotypes induced by STK25 overexpression, supporting GPX4 as a functional downstream effector. In xenografts, STK25 overexpression significantly suppressed tumor growth and increased ferroptosis-associated changes. These findings support an METTL3-STK25-YAP-GPX4 regulatory model that links epitranscriptomic control to ferroptosis susceptibility in OS and warrants further preclinical and prospective clinical validation.