LXR-α/SCD1-mediated Endoplasmic Reticulum-Mitochondria Crosstalk in Inhibiting Neuronal Ferroptosis after Spinal Cord Injury

作者：Pan Jiang, Yiqian Luo, Daoqiang Huang, Jiale He, Hongye Li, Longyou Xiao, Senyu Yao, Mao Pang, Limin Rong, Bin Liu · 发表于：Research · 年份：2025 · DOI：10.34133/research.1077 · 研究领域：Ferroptosis and cancer prognosis、Inflammasome and immune disorders、Cholesterol and Lipid Metabolism

Spinal cord injury (SCI) causes extensive neuronal loss, in which ferroptosis is critically involved. Although lipid transport at endoplasmic reticulum-mitochondria contact sites (ERMCSs) has been implicated in facilitating ferroptosis, the neuron-specific regulatory mechanisms remain elusive. Here, we show that neuronal ferroptosis is characterized by excessive ERMCS formation. Mechanistically, a systematic screening revealed the down-regulation of stearoyl-CoA desaturase 1 (SCD1), a critical enzyme in the synthesis of monounsaturated fatty acids (MUFAs) in neurons, following SCI (in vivo) or erastin treatment (in vitro). We demonstrated that SCD1 deficiency is the driving force behind aberrant ERMCS expansion, leading to increased lipid peroxidation and neuronal ferroptosis. Conversely, SCD1 overexpression could reverse these effects. Furthermore, we identified liver X receptor alpha (LXRα) as a direct transcriptional activator of SCD1. Pharmacological activation of LXRα with T0901317 upregulated SCD1 expression, which in turn restrained ERMCS formation, elevated MUFA levels, and ultimately inhibited neuronal ferroptosis. In murine SCI models, both adeno-associated virus-mediated neuronal SCD1 overexpression and LXRα agonist treatment effectively mitigated excessive ERMCS, reduced lesion size, preserved neuronal architecture, and improved functional recovery. Collectively, our study establishes the LXRα-SCD1 axis as a novel and druggable pathway for reducing neuronal loss a...