Low-intensity pulsed ultrasound regulates the osteogenic–adipogenic differentiation balance of rat adipose-derived stem cells via the PI3K/AKT-SREBF1 signaling axis

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Rat adipose-derived stem cells (rADSCs) are widely used in bone tissue engineering (BTE). Low-intensity pulsed ultrasound (LIPUS) can modulate stem cell fate; however, its precise regulatory effects on ADSC lineage commitment remain unclear. This study aimed to elucidate how LIPUS regulates the osteogenic-adipogenic differentiation balance of rADSCs. We first performed cell proliferation and differentiation induction assays, which demonstrated that LIPUS significantly enhanced osteogenic differentiation while simultaneously suppressing adipogenesis, without affecting rADSC proliferation. Subsequently, transcriptome sequencing and protein-protein interaction analysis identified sterol regulatory element binding transcription factor 1 (Srebf1) as a pivotal regulatory node in LIPUS-modulated osteogenic-adipogenic differentiation. Rescue experiments further confirmed that LIPUS rescued the Srebf1 overexpression phenotype by restoring osteogenic potential and attenuating adipogenesis. Mechanistically, LIPUS downregulated SREBF1 expression and inhibited its nuclear translocation by inhibiting PI3K/AKT signaling, as evidenced by synergistic effects with the PI3K-specific inhibitor LY294002. Finally, a rat cranial defect model was established to validate the osteogenic potential of LIPUS in vivo. LIPUS significantly enhanced bone defect repair, even in the presence of Srebf1-overexpressing rADSCs. Collectively, our findings suggest that SREBF1, a canonical transcription factor in lipid metabolism, also functions as a mechanoresponsive regulator in cell fate determination. Furthermore, LIPUS promotes bone regeneration by shifting the osteogenic-adipogenic differentiation balance in rADSCs toward osteogenesis through suppression of PI3K/AKT-SREBF1 pathway, thereby providing a potential therapeutic strategy for BTE.