Toxicological sciences : an official journal of the Society of ToxicologyOct 28, 2025

Removing a liver cell growth receptor reduces acetaminophen liver damage in mice

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Hepatocyte-specific EGFR deletion significantly attenuated liver injury progression at 12 and 24 hours after a toxic dose of acetaminophen.

EGFR deletion did not affect early liver injury at 6 hours post-acetaminophen administration.
Key injury events, such as the formation of acetaminophen-protein adducts and early JNK activation, remained unchanged in EGFR-deficient mice.
EGFR deletion limited prolonged JNK activation and mitochondrial damage, reducing the release of cell death drivers.
Replenishment of the antioxidant glutathione was faster in EGFR-deficient mice, potentially aiding in injury recovery.
RNA sequencing showed upregulation of autophagy and its regulator TFEB in EGFR-deficient mice, indicating a response to remove damaged mitochondria.
EGFR deletion also increased compensatory hepatocyte proliferation, possibly due to less severe liver injury.

Simplified

Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in liver. Our earlier investigations indicated a paradoxical cell-death promoting facet of EGFR in acetaminophen (APAP)-induced liver injury (AILI) model. The current study investigates this unexpected role of EGFR in promoting AILI using a hepatocyte-specific EGFR deletion mouse model. Hepatocyte-specific EGFR-deficient mice were generated by administering AAV8.TBG.Cre in EGFRfl/fl mice and were subsequently treated with a severely toxic dose (500 mg/kg) of APAP. Liver injury, regeneration and associated signaling pathways were assessed at different time intervals. EGFR deletion did not alter early liver injury at 6 hr but significantly attenuated the progression of liver injury at 12 and 24 hr following APAP overdose. Consistently, the key injury initiating events such as APAP-protein adducts formation and early JNK activation remained unimpaired in EGFR-deficient mice. However, EGFR deletion restricted prolonged JNK activation and its mitochondrial translocation, resulting in reduced propagation of mitochondrial damage and release of cell death drivers. Further, the replenishment of antioxidant glutathione (GSH), which is known to limit the progression of liver injury, was strikingly faster in EGFR-deficient mice. RNA-seq analysis and consequent validation revealed marked upregulation of autophagy and its transcriptional regulator TFEB, a key response to remove damaged mitochondria, in EGFR-deficient mice. Paradoxically, EGFR deletion also promoted compensatory hepatocyte proliferation possibly secondary to decreased severity of liver injury. Overall, hepatocyte-specific EGFR deletion halted the progression of AILI. Our study established an unexpected role of EGFR in promoting AILI progression, which has wide implications in liver biology.

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Removing a liver cell growth receptor reduces acetaminophen liver damage in mice

Abstract

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