Lim Jae Ryong, Chae Chang Woo, Yoon Jee Hyeon, Cho Ji Hyeon, Park Ji Yong, Han Su Jong, Chang Han Seung, Kim Su Yeol, Kim Ha Jin, Jung Young Hyun, Han Ho Jae
Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, 08826, South Korea.
Department of Physiology, and Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Int J Biol Sci. 2025 Aug 11;21(12):5167-5184. doi: 10.7150/ijbs.116673. eCollection 2025.
Endoplasmic reticulum (ER) stress is a major contributor to ethanol-induced neurodegeneration. ER-phagy, the selective elimination of specific ER domains, has emerged as a protective mechanism against ER stress. However, its regulation in ethanol-related neurological disorders remains unclear. Here, we investigated the effects and underlying mechanisms of ethanol on ER-phagy in neuronal cells and ethanol-fed mice. Our findings demonstrate that ethanol-induced ER stress is chronically sustained due to impaired ER-phagy. Among ER-phagy receptors, FAM134A expression was notably reduced by ethanol. Ethanol metabolism contributes to the downregulation of SIRT1 activity, leading to increased acetylation of histone H4 lysine 16 (H4K16ac) and enhanced recruitment of bromodomain-containing protein 4 (BRD4) to the FAM134A promoter. The BRD4/G9a complex-mediated increase in histone H3 lysine 9 dimethylation (H3K9me2) downregulates FAM134A expression by restricting the access of unfolded protein response (UPR)-associated transcription factor XBP1s. BRD4 inhibition or FAM134A overexpression restored ethanol-decreased ER-phagy, alleviating ER stress and preventing synaptic loss and neuronal cell death. In ethanol-fed mice, pharmacological inhibition of BRD4 restored hippocampal ER-phagy, resulting in improved cognitive function. In conclusion, recovering FAM134A-mediated ER-phagy through BRD4 inhibition may be a promising strategy to prevent ethanol-induced neurodegeneration.
内质网（ER）应激是乙醇诱导神经退行性变的主要促成因素。内质网自噬，即特定内质网结构域的选择性清除，已成为一种对抗内质网应激的保护机制。然而，其在乙醇相关神经疾病中的调节机制仍不清楚。在此，我们研究了乙醇对神经元细胞和乙醇喂养小鼠内质网自噬的影响及其潜在机制。我们的研究结果表明，由于内质网自噬受损，乙醇诱导的内质网应激会长期持续。在内质网自噬受体中，FAM134A的表达因乙醇而显著降低。乙醇代谢导致SIRT1活性下调，导致组蛋白H4赖氨酸16（H4K16ac）乙酰化增加，并增强含溴结构域蛋白4（BRD4）向FAM134A启动子的募集。BRD4/G9a复合物介导的组蛋白H3赖氨酸9二甲基化（H3K9me2）增加，通过限制未折叠蛋白反应（UPR）相关转录因子XBP1s的 access 来下调FAM134A的表达。抑制BRD4或过表达FAM134A可恢复乙醇降低的内质网自噬，减轻内质网应激，防止突触丢失和神经元细胞死亡。在乙醇喂养的小鼠中，对BRD4的药理学抑制恢复了海马体的内质网自噬，从而改善了认知功能。总之，通过抑制BRD4恢复FAM134A介导的内质网自噬可能是预防乙醇诱导神经退行性变的一种有前景的策略。
