{"doi":"10.1093/toxsci/kfaf151","title":"Hepatocyte-specific epidermal growth factor receptor (EGFR) deletion attenuates acetaminophen-induced liver injury in mice","abstract":"Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in the liver. Our earlier investigations indicated a paradoxical cell-death-promoting facet of EGFR in the 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 h but significantly attenuated the progression of liver injury at 12 and 24 h 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, transcription factor EB, 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.","journal":"Toxicological Sciences","year":2025,"id":536993,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1407734,"name":"Gillian Williams","orcid":null,"position":1,"is_corresponding":false},{"id":1407222,"name":"Ranjan Mukherjee","orcid":"0000-0002-7211-1362","position":2,"is_corresponding":false},{"id":118349,"name":"Anne Orr","orcid":null,"position":3,"is_corresponding":false},{"id":1407223,"name":"Jiajun Liu","orcid":"0009-0007-0699-5917","position":4,"is_corresponding":false},{"id":279404,"name":"Silvia Liu","orcid":"0000-0002-1840-9520","position":5,"is_corresponding":false},{"id":465703,"name":"Joseph Locker","orcid":"0000-0002-4190-188X","position":6,"is_corresponding":false},{"id":364927,"name":"Bharat Bhushan","orcid":"0000-0002-1716-9764","position":7,"is_corresponding":false},{"id":1261020,"name":"Siddhi Jain","orcid":"0000-0001-5452-7180","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:52:09.056872Z","pmid":"41148051","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}