Recovery of FAM134A-mediated ER-phagy through BRD4 inhibition alleviates ethanol-induced neurodegeneration

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.