Inflammasome Activation as a Key Driver of Acetaminophen-induced Hepatotoxicity: Mechanisms and Emerging Therapeutics (IMAGE)
Caption
Acetaminophen-induced liver injury remains a significant global public health concern due to its potential to cause acute liver failure and mortality in severe cases. The hepatotoxic effects of APAP are primarily mediated by its bioactivation to the reactive metabolite NAPQI via CYP2E1. Excessive accumulation of NAPQI depletes hepatic GSH stores, leading to oxidative stress, mitochondrial dysfunction, and covalent modification of cellular macromolecules. Multiple regulated and unregulated cell death pathways contribute to APAP-induced hepatotoxicity, including necrosis, apoptosis, necroptosis, and pyroptosis. Among these, sterile inflammation plays a pivotal role in amplifying liver injury. Inflammasome complexes, particularly NLRP3, have emerged as key regulators of this inflammatory response. Activation of the NLRP3 inflammasome leads to the cleavage of procaspase-1 into its active form, which in turn processes proinflammatory cytokines such as IL-1β and IL-18 and drives pyroptotic cell death via Gasdermin D activation. Despite the availability of NAC as the primary therapeutic agent for APAP overdose, treatment options remain limited, particularly when administered beyond the early therapeutic window. Consequently, current research has focused on identifying novel therapeutic strategies targeting the inflammatory and cell death pathways involved in APAP-induced hepatotoxicity. These include direct inhibition of inflammasome components, caspase-1 blockade, modulation of immune responses using anti-inflammatory agents, and targeted manipulation of gut microbiota and bile acid metabolism, which are increasingly recognized for their roles in liver homeostasis and injury response. Pharmacological inhibitors such as NLRP3 antagonists and caspase-1 inhibitors show promise in preclinical models but require further clinical validation. Emerging strategies targeting the gut-liver axis, such as microbiome modulation and bile acid receptor agonists, also offer new therapeutic avenues for APAP-induced liver injury. However, a deeper understanding of the molecular mechanisms leading to APAP-induced liver injury is crucial for developing effective, timely, and targeted therapies to reduce the global burden of APAP toxicity.
Credit
Latchoumycandane Calivarathan
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CC BY-NC