Mesencephalic astrocyte-derived neurotrophic factor protects against paracetamol -induced liver injury by inhibiting PERK-ATF4-CHOP signaling pathway

Paracetamol (APAP), an over-the-counter drug, is normally safe within the therapeutic dose range but can cause irreversible liver damage after an overdose. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress protein and plays a crucial role in metabolic disease. However, the role of MANF in APAP-induced acute hepatotoxicity is still unknown. We used hepatocyte-specific MANF-knockout mice and hepatocyte-specific MANF transgenic mice to investigate the role of hepatocyte-derived MANF in APAP-induced acute liver injury. MANF deficiency was associated with a decreased expression of detoxification enzymes, aggravated glutathione depletion and apoptosis in hepatocytes. Mechanistically, MANF knockout significantly increased PERK-eIF2α-ATF4-CHOP signaling pathway. Blockade of PERK abolished MANF deficiency-over-induced hepatotoxicity after APAP administration. Conversely, hepatocyte-specific MANF overexpression attenuated APAP-induced hepatotoxicity by downregulating the PERK-eIF2α-ATF4-CHOP signaling pathway. Thus, hepatocyte-derived MANF may play a protective role in APAP-induced hepatotoxicity.