Activating transcription factor 3 alleviates acute liver injury in mice by inhibiting endogenous retroelements

Activating transcription factor 3 (ATF3) plays a dual role in hepatic pathophysiology, particularly in its well-established involvement in activating hepatic stellate cells and promoting liver fibrosis in chronic liver disease. However, the role of ATF3 and its molecular mechanisms in acute liver injury remain unclear, despite the urgent need for effective therapeutic strategies for this condition. This study aimed to elucidate the protective role of ATF3 and its underlying mechanisms in acute liver injury. We utilized a carbon tetrachloride (CCL₄)-induced acute liver injury mouse model and hepatic stellate cells (HSCs) as an in-vitro model. Our findings demonstrate that ATF3 overexpression significantly alleviates early symptoms of acute liver injury, including reduced inflammation and improved liver function, leading to a better prognosis. Mechanistically, we discover that ATF3 exerts its protective effects by inhibiting the aberrant activation of endogenous retroelements (EREs). This inhibition prevents ERE-induced genomic instability and the subsequent activation of the cGAS/STING innate immune pathway, thereby suppressing the production of pro-inflammatory cytokines such as interferon-beta (IFNβ). Further analysis reveals that ATF3 directly binds to the promoter regions of EREs, transcriptionally repressing their expression. In summary, this study identifies ATF3 as a critical negative regulator of ERE activation in acute liver injury, elucidating a novel mechanism by which ATF3 mitigates inflammation and promotes hepatic repair through ERE regulation. These findings suggest that targeting the ATF3-ERE axis represents a promising therapeutic strategy for acute liver injury and enhances our understanding of how transcription factors modulate innate immune responses through interaction with EREs.