MET Signaling’s Protective Role Shows Promise for Treating Acetaminophen-Induced Acute Liver Failure

A new study has found that MET (hepatocyte growth factor receptor) signaling plays a critical protective role in acetaminophen-induced acute liver failure (ALF). This pathway is shown to work as a dual-action mechanism that both reduces liver damage and accelerates regeneration. The findings from a novel studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, suggest that targeting MET signaling could become a game-changer for the treatment of drug-induced ALF.

Acetaminophen (N-acetyl-p-aminophenol; APAP) is one of the most used over-the-counter analgesic and antipyretic medications worldwide. However, accidental or intentional APAP overdose remains the major cause of drug-induced liver injury. It is a leading contributor to ALF in the Western world, accounting for nearly half of all ALF cases in the United States, with around 80,000 APAP overdose cases presenting to hospitals annually. Recovery from APAP-induced acute liver injury critically depends on the liver’s ability to regenerate.

MET signaling is well established as a central driver of liver regeneration after surgical resection of the liver. Yet, its specific role during toxic liver injury, where massive necrosis and inflammation profoundly alter the regenerative landscape, remains unclear. This study examined how hepatocyte-specific MET deletion affects liver injury and compensatory regeneration after APAP overdose in a clinically relevant mouse model.

Lead investigator Bharat Bhushan, PhD, Department of Pathology, University of Pittsburgh School of Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh, explains, “We found that MET deficiency dramatically worsened APAP overdose-induced liver injury by allowing toxic stress signals (c-Jun N-terminal kinase; JNK) to attack the mitochondria, the cell’s metabolic hubs. Crucially, the absence of MET also severely impaired the liver's regeneration. By activating survival pathways like AKT (protein kinase B), we were able to reduce this damage, proving that MET is essential for both protecting and repairing the liver after a drug-induced overdose. Importantly, our analysis of human acute liver failure datasets confirms that these findings are clinically relevant.”

Therapeutic options remain extremely limited for acetaminophen-induced ALF. N-acetyl cysteine (NAC) has been the only approved pharmacological therapy for decades, but it is not effective in late presenting patients, who represent the majority of clinical cases. Since ALF progresses very quickly, in a scenario in which NAC therapy does not work, liver transplantation is the only other effective option, which is limited by organ availability. Around 30% of APAP-induced ALF cases result in death.

First author Siddhi Jain, Department of Pathology, University of Pittsburgh School of Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh, notes, “There is an urgent need for novel therapies that go beyond the time window when NAC is effective. Our research is novel because it identifies MET signaling as a central pathway that not only restricts liver damage but also drives recovery, providing a promising dual therapeutic target. Every discovery brings us one step closer to better treatments for patients who need them most."

"This work reflects a commitment to turning scientific insight into meaningful progress for patients," adds Dr. Bhushan. “Therapies that boost the activity of MET may offer a critical lifeline, especially when current treatments like NAC fall short.”

Notes for editors

The article is “Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice,” by Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza AP Faccioli, Zhiping Hu, Rodrigo M. Florentino, George K. Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, and Bharat Bhushan (https://doi-org.ucc.idm.oclc.org/10.1016/j.ajpath.2025.09.010opens in new tab/window). It appears in The American Journal of Pathology, volume 196, issue 2 (February 2026), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(25)00367-0/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact: Bharat Bhushan, PhD, at [email protected]opens in new tab/window.

This work was supported by National Institutes of Health (NIH) grant R01 DK135566, and also in part by NIH grant R01 DK122990, the Pittsburgh Liver Research Center NIH grant P30 DK120531, and the University of Pittsburgh Center for Research Computing and Data (RRID:SCR_022735) through the resources provided. Specifically, this work used the High-Throughput Computing cluster, which is supported by NIH award number S10OD028483.

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.orgopens in new tab/window

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