C109-01 LncRNA SNHG1-as1 Alleviates Intermittent Hypoxia-induced Neuroinflammation by Stabilizing SLC3a2 mRNA to Inhibit Microglial Ferroptosis

Abstract Rationale Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is a key contributor to OSA-related neuroinflammation and cognitive impairment. Oxidative stress is a central mediator of neuroinflammatory cascades, while ferroptosis—an iron-dependent cell death closely linked to oxidative stress—has emerged as a major pathogenic mechanism. Long noncoding RNAs (lncRNAs) have been implicated in ferroptosis regulation; however, their roles in CIH-induced neuroinflammation remain largely unknown. Methods BV2 cells exposed to IH or normoxia underwent lncRNA sequencing, identifying ferroptosis as a key enriched pathway. Ferroptosis inducer erastin and inhibitor ferrostatin-1 (Fer-1) were applied to assess ferroptotic involvement. Mitochondrial morphology was examined by transmission electron microscopy, and apoptosis levels and ferroptosis indices (ROS, lipid peroxidation, SOD, MDA, GSH/GSSG) were quantified. C57BL/6J mice were subjected to IH or normoxia for 4 weeks with or without erastin or Fer-1. Cognitive function was tested by fear conditioning and Morris water maze. Hippocampal sections underwent H&E, NeuN, IBA1, DHE, and TUNEL staining, with quantification of iron accumulation, ROS, MDA, and proinflammatory cytokine mRNA levels. SNHG1, the most altered lncRNA, was validated by qPCR and functionally characterized via knockdown or overexpression. Dual-luciferase, RNA pull-down, and Actinomycin D assays examined the SNHG1-FXR2-SLC3A2 axis, and AAV-mediated SNHG1 overexpression was tested in vivo. Results LncRNA sequencing of IH-exposed BV2 cells identified ferroptosis as a major enriched process. By establishing an IH-induced BV2 cell model, we observed that IH triggered ferroptotic mitochondrial morphology, elevated ROS, lipid peroxidation, and MDA, alongside reduced SOD and GSH/GSSG ratio. Fer-1 alleviated, whereas erastin exacerbated, oxidative stress and apoptosis, confirming ferroptosis as a key driver of IH-induced microglial activation. In vivo, IH impaired spatial learning and memory, accompanied by hippocampal oxidative stress, iron accumulation, microglial activation, and neuronal apoptosis—all reversed by Fer-1 and aggravated by erastin. Among ferroptosis-related lncRNAs, SNHG1 showed the most pronounced change and was selected for further study. SNHG1 overexpression mitigated, whereas its silencing aggravated, IH-induced microglia oxidative stress and ferroptosis. Mechanistically, SNHG1 stabilized SLC3A2 mRNA through interaction with RNA-binding proteins, FXR2, thereby enhancing system Xc1 activity and suppressing ferroptosis. AAV-mediated SNHG1 overexpression in vivo alleviated hippocampal microglial ferroptosis and neuroinflammation under IH exposure. Conclusion We demonstrate that lncRNA SNHG1 alleviates IH-induced neuroinflammation by stabilizing SLC3A2 mRNA through FXR2, maintaining system Xc1 function and inhibiting ferroptosis. These findings reveal a novel SNHG1/FXR2/SLC3A2 axis and suggest SNHG1 as a potential therapeutic target for OSA-related cognitive impairment. This abstract is funded by: the National Natural Science Foundation of China (Grant no. 82200102 & 82202688)