Hepatocyte IER2 attenuates APAP-induced liver injury by regulating ACOT2-mediated lipid metabolism in mice.

Acetaminophen (APAP)-induced liver injury (AILI) is a common serious adverse drug event, yet its molecular mechanisms remain incompletely understood. To identify key regulators in AILI, we conduct a temporal liver transcriptomic sequencing analysis in mice subjected to APAP exposure, revealing a significant and dynamic alteration in the expression of immediate early response 2 ( Ier2). Single-cell RNA sequencing analysis further delineates Ier2 expression patterns across hepatic cell populations following APAP insult. Hepatocyte-specific Ier2 knockout (HKO) mice and hepatocyte-directed Ier2 overexpression mice are generated to elucidate the molecular function of IER2 in AILI. RNA sequencing and proteomics are performed to investigate the underlying protective mechanisms of IER2 in AILI. We demonstrate that hepatocyte-specific Ier2 deletion increases susceptibility to AILI, whereas hepatic Ier2 overexpression ameliorates APAP-induced liver injury. Integrated transcriptomic and proteomic analyses identify lipid metabolism as a key pathway modulated by IER2 overexpression, with ACOT2 as a putative target. Functional rescue experiments reveal that ACOT2 knockdown markedly attenuates the protective effect of IER2, indicating that ACOT2 is required for IER2-mediated hepatoprotection. In conclusion, IER2 protects against AILI by modulating lipid metabolism pathways, with ACOT2 as a critical downstream effector. These findings position IER2 as a promising and novel therapeutic target for mitigating AILI.