Yang D, Kim B, Kim JW. Mechanistic insights into hepatic cell type-specific contributions to acetaminophen-induced acute liver injury. World J Gastroenterol 2025; 31(45): 112720 [PMID: 41378327 DOI: 10.3748/wjg.v31.i45.112720]
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03769692
Submitted on:
December 03, 2025, 16:27
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Reader Comments:
This review elevates our understanding of acetaminophen (APAP)-induced acute liver injury from a “single toxic metabolite acting on hepatocytes” model to a dynamic network involving multiple hepatic cell populations. Second, it clearly maps out current and potential therapeutic targets, essentially providing a “cell-type–oriented treatment roadmap” for future translational work. The discussion of CYP2E1/CYP3A4, species differences, and risk factors (such as alcohol use, malnutrition, underlying liver disease, and concomitant enzyme-inducing drugs) helps clinicians better identify high-risk populations and appreciate the limitations of extrapolating from animal models, thereby supporting more individualized risk assessment and dosing. In the treatment section, the authors extend beyond the classical “N-acetylcysteine golden window” and cover emerging strategies such as inhibition of NAPQI formation (e.g. fomepizole), mitochondria-targeted antioxidants (Mito-Tempo, MitoQ), modulation of ferroptosis/ferritinophagy, NLRP3–STING inflammasome pathways, as well as cell-based and hepatocyte transplantation therapies. This allows clinical readers to quickly grasp potential combination or alternative approaches that are entering or approaching clinical trials, while signaling to basic scientists multiple promising cellular pathways and targets for deeper exploration. Overall, the article reads as an up-to-date progress review on the multicellular mechanisms and therapeutic targets of APAP-induced acute liver injury, offering both mechanistic clarity and topic inspiration for those working on drug-induced liver injury, emergency/critical care, and liver transplantation—while also realistically emphasizing that most of the evidence remains at the experimental or early translational stage and is not yet ready to change clinical guidelines.