DEGS1-mTORC1-driven lipid metabolic reprogramming fuels rhabdomyosarcoma progression and unveils a therapeutic vulnerability

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and adolescents, is a malignant tumor of skeletal muscle histogenesis that remains one of the most difficult pediatric cancers to cure. Here, we identify ifc, the Drosophila orthologue of DEGS1, as a key regulator of muscle stem cells (MuSCs). Ifc/DEGS1 encodes a sphingolipid desaturase that converts dihydroceramide to ceramide during ceramide biosynthesis. In Drosophila, ifc overexpression expands MuSC populations and suppresses differentiation, mirroring RMS like properties. Consistently, DEGS1 is upregulated in RMS cells, where it drives lipid droplet biogenesis and activates mTORC1 signaling to inhibit lipophagy, leading to aberrant lipid droplet accumulation. This metabolic rewiring positions lipid droplets, which have been largely overlooked in RMS biology, as central hubs that promote proliferation, suppress differentiation, and enhance metastatic potential, thereby driving RMS progression. Importantly, dual pharmacologic inhibition of DEGS1 and mTORC1 synergistically suppresses tumor growth and metastasis, revealing a lipid droplet–dependent vulnerability in RMS. Together, our findings establish a mechanistic link between sphingolipid metabolism, mTORC1-mediated regulation of lipophagy, and tumor aggressiveness, highlighting lipid droplet metabolism as a tractable therapeutic target in RMS. Rhabdomyosarcoma is an aggressive childhood cancer with limited treatment options for advanced disease. Here, the authors show that the ceramide-pathway associated enzyme DEGS1 regulates muscle stem cells inducing tumor progression through mTORC1 and lipid metabolism, revealing a target for rhabdomyosarcoma.