Mol Biotechnol. 2025 Sep 4. doi: 10.1007/s12033-025-01499-1. Online ahead of print.
ABSTRACT
BACKGROUND AND OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is a common sleep breathing disorder, and nonalcoholic fatty liver disease (NAFLD) may affect OSAS. This study aimed to explore the influence of exosomes (Exos) derived from liver cells in NAFLD on the progression of OSAS and the underlying molecular mechanisms.
METHODS: C57BL/6J mice were exposed to chronic intermittent hypoxia (CIH) to establish an OSAS animal model, and SH-SY5Y cells treated with CIH were used as the in vitro cellular model. THLE-2 cells treated with oleic acid (OA) were used to simulate NAFLD, and Exos were isolated from these cells. The morphological characteristics of Exos were observed by transmission electron microscopy (TEM), and their particle size distribution and concentration were determined by nanoparticle tracking analysis (NTA). Furthermore, potential binding sites between lncRNA MALAT1 and miR-579-3p, as well as between miR-579-3p and Keap1 mRNA, were predicted using the starBase database. HE staining was used to assess histopathological damage in mouse hippocampal tissues, and TUNEL staining was performed to assess neuronal apoptosis.
RESULTS: Exos derived from OA-treated THLE-2 cells significantly upregulated the expression of oxidative stress markers (ROS and MDA) and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) while downregulating the activity of antioxidant factors, including SOD and GSH. These alterations exacerbated neuronal damage in both the hippocampal tissues of OSAS mice and CIH-induced SH-SY5Y cells. Mechanistically, the lncRNA MALAT1 was markedly upregulated in Exos, which promoted Keap1 expression and suppressed Nrf2 expression through MALAT1 delivery, thereby activating the Keap1/Nrf2 signaling pathway. Furthermore, MALAT1 was observed to bind and downregulate miR-579-3p expression, consequently relieving its inhibitory effect on Keap1 and ultimately aggravating neuronal injury in OSAS mice.
CONCLUSION: Exosomal lncRNA MALAT1 derived from NAFLD hepatocytes exacerbates OSAS-associated neuronal injury by suppressing miR-579-3p expression and subsequently activating the Keap1/Nrf2 signaling pathway. This discovery not only reveals the molecular link between NAFLD and OSAS-induced neurological damage but also provides critical insights into the pathogenesis of OSAS and potential therapeutic strategies.
PMID:40906321 | DOI:10.1007/s12033-025-01499-1