Novel lipid metabolism factor HIBCH inhibitor synergizes with doxorubicin to suppress osteosarcoma growth and impacts clinical prognosis in osteosarcoma patients

•This study investigates the role of HIBCH in osteosarcoma and evaluates the therapeutic potential of HIBCH inhibitor SBF-1.•Through experiments, we demonstrated that HIBCH promotes osteosarcoma malignancy by regulating the TCA cycle, and its inhibitor SBF-1 effectively suppresses tumor growth via the Akt-mTOR pathway.•Notably, SBF-1 shows synergistic anti-tumor effects when combined with doxorubicin both in vitro and in vivo.•These findings provide a novel therapeutic strategy for osteosarcoma treatment through targeting HIBCH. Osteosarcoma (OS) is a highly malignant primary bone tumor primarily affecting children and adolescents. Despite advancements in therapeutic strategies, long-term survival rates for OS remain unfavorable, especially in advanced or recurrent cases. Emerging evidence has noted the involvement of lipid metabolism dysregulation in OS progression, but the specific mechanisms remain unclear. A risk model incorporating lipid metabolism-related genes was established to stratify OS patients into high-risk and low-risk groups. Functional assays were conducted to assess the role of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in OS cell activities. Ultra-fast liquid chromatography-mass spectrometry was adopted to analyze the impact of HIBCH on OS cell metabolism. Moreover, the combined effect of HIBCH inhibitor SBF-1 with doxorubicin (DOX) was evaluated through in vitro studies and mouse xenograft models. HIBCH was identified as a key gene involved in the malignant behaviors of OS cells. HIBCH knockdown disrupted tricarboxylic acid (TCA) cycle activity and reduced oxidative phosphorylation in OS cells. SBF-1 showed synergistic effects with DOX in inhibiting malignant phenotypes of OS cells by modulating the Akt-mTOR pathway. In vivo experiments demonstrated that the combination of SBF-1 and DOX significantly suppressed tumor growth in mouse xenograft models. This study reveals the critical role of lipid metabolism in OS progression and suggests a new therapeutic strategy against chemotherapy resistance in OS based on the synergistic combination of SBF-1 with DOX.