Nutrient flux governs osteogenic fate commitment through the SLC3A1-cystine Axis

Skeletal and mesenchymal cells have limited bone-forming potential due to their rarity, tendency for senescence and/or unstable osteogenic lineage commitment. We previously identified an osteopotent CXCR4 stem cell population with unclear mechanism for its differentiation potential. Here, we found that the cystine transporter SLC3A1 was selectively enriched in CXCR4+ stem cells, uncovering a role for amino acid transport in regulating osteogenic fate commitment. Enforced SLC3A1 expression reprogrammed mesenchymal cells toward a stable osteogenic state while suppressing adipogenic differentiation. Mechanistically, SLC3A1-mediated cystine flux established a glutathione-dependent metabolic program that preserved mitochondrial fitness and restrained stem cell senescence. SLC3A1 also stabilized IGF-1 through suppression of ZMYND8-mediated ubiquitination, uncovering ZMYND8 as a previously unrecognized E3 ligase regulating osteogenic commitment. Cystine supplementation phenocopied the effects of SLC3A1 activation, promoting osteogenic differentiation and skeletal regeneration without genetic manipulation. In vivo, cystine administration accelerated bone regeneration and attenuated ovariectomy-induced bone loss, while analyses of a human osteoporosis cohort, osteoporotic specimens, and single-cell transcriptomic datasets revealed coordinated suppression of the SLC3A1-cystine-IGF-1 pathway in osteoporotic mesenchymal cells. Taken together, these findings establish SLC3A1-mediated cystine transport as a programmable metabolic determinant of osteogenic fate commitment and identify cystine metabolism as a therapeutically targetable axis for skeletal regeneration and osteoporosis.