mTORC1-regulated LDL receptor increasing and oxidized lipid accumulation in osteocytes participate in trauma-induced osteonecrosis of the femoral head.

Osteocyte apoptosis induced by hypoxia and ischemia represents a central pathological hallmark of trauma-induced osteonecrosis of the femoral head (TIONFH). Increasing evidence further implicates lipid metabolism disturbance in femoral heads as a critical contributor. However, the underlying molecular mechanisms, especially the lipid metabolism in osteocytes, remain poorly defined. We demonstrate for the first time that severe hypoxia in TIONFH drives oxidized lipid accumulation and cell apoptosis in osteocytes via coordinated activation of the mTORC1/LDLR axis. In vitro and in vivo studies prove that hypoxia elicits LDL/ox-LDL accumulation by activating mTORC1, which promotes SREBP2 upregulation and SCAP-SREBP2 translocation to the Golgi complex, thereby enhancing LDLR synthesis; while concurrently suppressing PCSK9-mediated LDLR degradation, ultimately resulting in excessive LDL uptake. Under hypoxic conditions, intracellular LDL/ox-LDL tends to propagate through the lacunar-canalicular network to initiate a cascade of osteocyte death. Notably, pharmacological inhibition of mTORC1 with rapamycin effectively reverses these effects and osteocyte death cascade. Collectively, our findings define a previously unrecognized mTORC1/LDLR axis linking hypoxia to lipid accumulation and osteocyte apoptosis in TIONFH, and highlight a potential target for early-stage TIONFH prevention and treatment.