ENAGenomicsBoYu Intelligent Health Innovation Laboratory, Hangzhou, 311100, P. R. China.https://www.ebi.ac.uk/ena/browser/view/PRJNA1163013Mus musculusxref:PubMed:40596188Osteosarcoma (OS) is a severe malignancy affecting children and adolescents, with limited effective treatments leading to poor outcomes. This study explored the potential of sporoderm-removed Ganoderma lucidum spores (RGLS) as a novel therapeutic agent against OS and elucidated its mechanism of action. Our in vivo and in vitro experiments showed that RGLS significantly inhibited S-180 OS cell proliferation, colony formation, and migration, while simultaneously inducing apoptosis. Multi-omics analysis revealed that RGLS disrupted glycerophospholipid metabolism by upregulating lysophosphatidylcholine (LysoPC) levels through phospholipase A2 (PLA2)-mediated pathways. Co-culture assays further demonstrated that RGLS promoted the endocytosis of macrophage-derived Pla2g7 protein into S-180 cells, enhancing its anti-cancer effects. Additionally, RGLS modulated the cellular fatty acid profile and suppressed the β-oxidation of long-chain fatty acids, leading to energy depletion in OS cells. These findings provide a novel view of the multi-targeted mechanisms of RGLS, positioning it as a promising candidate for OS therapy. Overall design: We administered RGLS prophylactically to BALB/c nude mice and then injected them subcutaneously with S-180 cells to evaluate RGLS's tumor-inhibiting effects. We then extracted tissues from three model samples and three RGLS processed samples for RNA-seq.ENAfalseMulti-omics analysis reveals inhibition of osteosarcoma progression by sporoderm-removed ganoderma lucidum spores via targeting glycerophospholipid and fatty acid MetabolismMulti-omics analysis reveals inhibition of osteosarcoma progression by sporoderm-removed ganoderma lucidum spores via targeting glycerophospholipid and fatty acid Metabolism2025-09-242025-07-17PRJNA1163013GSE2776331009040596188