Single-cell and multi-omics integrative modeling identifies mitochondrial gene HSPE1 as a therapeutic target in osteosarcoma.

BACKGROUND: Mitochondrial metabolism plays a critical role in tumor growth and progression. However, its specific influence on osteosarcoma prognosis remains unclear. METHODS: We conducted univariate Cox regression analysis to identify mitochondrial genes associated with osteosarcoma prognosis. Subsequently, prognostic models predicting overall survival were built using a comprehensive combination of 101 hybrid and 10 machine learning algorithms. In addition, we also evaluated the relationship between the best prognostic model clustering and the clinical characteristics, functional progression, immune microenvironment and immunotherapy of osteosarcoma. Single-cell analysis showed the differences of cell communication in high and low model scores. The expression of the key gene HSPE1 was verified by PCR and immunoblotting in clinical samples. In osteosarcoma cells, HSPE1 was knocked out to verify its effects on osteosarcoma cell proliferation, migration, apoptosis and in vivo tumorigenesis. RESULTS: The mitochondrial prognostic index model we constructed is an independent prognostic marker for osteosarcoma, and its ability to predict prognosis is superior to other clinical characteristics and published prognostic features. The high-scoring group was significantly associated with immunosuppression and poor prognosis of immunotherapy, and the signaling pathways that promote tumor progression were significantly enriched. Single-cell analysis showed that TIL infiltration was significantly reduced in the high-scoring group, and CD74-CXCR4 was the main contributing signaling pathway. HSPE1 was identified as a potential therapeutic target for osteosarcoma. PCR and immunoblotting experiments verified that it was highly expressed in osteosarcoma tissues. Knockdown of HSPE1 significantly reduced osteosarcoma cell migration, proliferation, metastasis potential, and increased apoptosis rates. In vivo studies confirmed markedly decreased tumorigenicity following HSPE1 knockout. CONCLUSIONS: MIscore reliably identifies high-risk osteosarcoma subgroups. HSPE1 promotes osteosarcoma progression, correlates with immunosuppression, and represents a novel therapeutic target for personalized treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07633-6.