FAM134B-mediated ER-phagy alleviates alcohol-related liver fibrosis by reducing endoplasmic reticulum stress

Alcohol-related liver fibrosis (ALF), a severe stage of alcohol-related liver disease (ALD), currently lacks effective treatments. Endoplasmic reticulum (ER) stress is a key pathological feature of ALF. FAM134B (JK-1, RETREG1), an ER-phagy receptor, mediates ER-phagy to alleviate ER stress and restore ER homeostasis. However, the molecular mechanisms linking ER stress to ALF remain unclear.

This study aimed to investigate the role and molecular mechanisms of FAM134B in ALF, specifically whether FAM134B-mediated ER-phagy reduces ER stress to mitigate ALF.

We developed a FAM134B overexpression mouse model using tail vein injection of AAV-8-TBG-m-FAM134B and monitored disease progression in ALF mice. Fibrosis markers (α-SMA, COL1A1), ER stress indicators (GRP78, CHOP, IRE1-α, ATF6), and ER-phagy markers (LC3, p62, VAPB, CANX, Climp63, REEP5) were analyzed. Additionally, further in vitro experiments were carried out to explore whether FAM134B-mediated ER-phagy attenuates ALF by alleviating hepatocyte ER stress.

FAM134B overexpression increased ER-phagy, reduced ER stress, and ameliorated liver fibrosis. In vitro, FAM134B overexpression promoted autophagy, decreased cytokine secretion, and inhibited hepatic stellate cell (JS-1) and macrophage activation (RAW264.7).

These findings suggest that FAM134B-mediated ER-phagy mitigates ALF by alleviating ER stress, providing new targets and intervention strategies for ALF.