Ming-Zhi Huang,Hong-Yan Chen,Guo-Xuan Peng,Hong Sun,Hong-Cheng Peng,Hai-Yang Li,Xiang-Hui Liu,Qing Li
Aim: Effect of artesunate (ART)-treated bone marrow-derived mesenchymal stem cells-derived exosomes (BMSC-Exos) on osteogenesis and its underlying mechanisms were investigated. Materials & methods: Proliferation, alkaline phosphatase activity and calcified nodule formation of osteoblasts were determined. A mouse model of osteoporosis was established by ovariectomy. Results:SNHG7 was upregulated in BMSC-Exos by twofold, which was further enhanced in ART-BMSC-Exos by about twofold. ART intensified BMSC-Exos-induced proliferation, alkaline phosphatase activity by about fourfold, calcified nodule formation by about threefold and upregulation of osteogenesis related molecules RUNX2 (by 50%), BMP2 (by 30%) and ATF4 (by 40%) via delivering SNHG7. Mechanistically, SNHG7 recruited TAF15 to facilitate RUNX2 stability. Conclusion: ART-BMSC-Exos facilitated osteogenesis via delivering SNHG7 by modulating TAF15/RUNX2 axis.Plain language summaryOsteoporosis is the most common and complex skeletal disorder worldwide. Exosomes derived from bone marrow-derived mesenchymal stem cells (BMSC-Exos) have been recognized as an ideal seed source for bone tissue regeneration. We aimed to explore the effect of artesunate (ART)-BMSC-Exos on osteogenesis and its underlying mechanisms. The results showed that ART-BMSC derived exosomal SNHG7 facilitated osteoblast activity and attenuated osteogenesis in mice by modulating TAF15/RUNX2 pathway. Our findings contribute to a better understanding of the therapeutic mechanisms of ART-BMSCs-Exos for osteoporosis and suggest ART-BMSC-Exos as a novel therapeutic option for osteoporosis.
IDH mutant gliomas, driven by the oncometabolite 2-hydroxyglutarate (2-HG), are associated with profound neurological morbidity and premature mortality. To address the unmet therapeutic needs, we investigated the mechanistic interplay between MTHFD2-driven one-carbon metabolism and ferroptosis susceptibility in these tumors. Our findings revealed that MTHFD2 upregulation, mediated through loss of m5C modification in chromatin associated RNAs (caRNAs)-establishes a metabolic vulnerability to ferroptosis. Crucially, we identified TAF15 as a pivotal RNA-binding protein that orchestrates the spatial recruitment of TET2 by bridging NSUN5-mediated RNA m5C methylation. Therapeutically, combinatorial targeting of MTHFD2 with its selective inhibitor and the hypomethylating agent decitabine induced ferroptosis in patient-derived IDH-mut glioma organoids, demonstrating potent ferroptosis activation. This work delineates an RNA epitranscriptomic-metabolism axis in glioma pathogenesis and provides a translational roadmap for exploiting metabolic dependencies in IDH-driven malignancies. CLINICAL TRIAL NUMBER: Not applicable.
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