Antimony- and NSAID-Induced Hepatotoxicity at the Molecular Crossroads: Redox, Inflammasome and Programmed Cell-Death Networks as Therapeutic Targets for Natural Hepatoprotective Agents.

Abstract

Drug- and metal-induced liver damage (DILI/MILI) continues to be a predominant cause of acute hepatic failure globally, with two clinically significant but mechanistically underexplored triggers being the metalloid antimony (Sb) and non-steroidal anti-inflammatory medications (NSAIDs). This review consolidates current molecular findings about the convergence of Sb(III)/Sb(V) species and NSAID reactive metabolites on a common hepatotoxic framework. Hepatic organic anion-transporting polypeptides and multidrug-resistance proteins regulate the sinusoidal uptake and canalicular efflux of both substances, while cytochrome P450 2C9/3A4/2E1-mediated bioactivation of NSAIDs and thiol-reactive Sb species produces reactive oxygen species (ROS), diminishes reduced glutathione (GSH) levels, disrupts mitochondrial membrane potential and initiates PERK-eIF2α-ATF4-CHOP-mediated endoplasmic reticulum stress. These insults target nuclear factor-kappa B, mitogen-activated protein kinase and NLRP3 inflammasome signalling, resulting in apoptotic, necroptotic, pyroptotic and ferroptotic hepatocyte death. We conduct a comprehensive assessment of the multi-target hepatoprotective effects of polyphenols (curcumin, resveratrol, quercetin), flavonoids, terpenoids, alkaloids and extracts from medicinal plants, focusing on the activation of the Nrf2/Keap1/ARE antioxidant pathway, inhibition of NF-κB and NLRP3, AMPK-SIRT1-PGC-1α-mediated mitochondrial biogenesis, PI3K/Akt cytoprotective signalling and PINK1/Parkin-dependent mitophagy. We ultimately examine translational prospects, including omics-derived hepatotoxicity biomarkers, network pharmacology, artificial intelligence-facilitated natural product discovery, nanocarrier-mediated hepatoprotective administration and precision medicine strategies for the prevention of drug-induced liver injury (DILI). The intersection of antimony- and NSAID-induced damage at a limited number of druggable targets supports the use of multi-target natural therapies as logical complements to traditional hepatoprotection. However, the strength of evidence supporting this convergence is heterogeneous: Several downstream mechanisms-particularly NLRP3 inflammasome activation, ferroptosis, pyroptosis and necroptosis in antimony-induced hepatotoxicity-are supported mainly by in vitro and animal data rather than confirmed human evidence, and are treated in this review as emerging or hypothetical rather than established. As this is a narrative rather than a systematic review, the literature search strategy, evidence-grading approach and limitations are described explicitly to aid transparent interpretation.

Key Findings

• Antimony and NSAIDs induce hepatotoxicity via generation of reactive oxygen species (ROS) and depletion of reduced glutathione (GSH), leading to oxidative stress and mitochondrial dysfunction.
• Hepatocyte death from these insults involves multiple programmed cell death pathways including apoptosis, necroptosis, pyroptosis, and ferroptosis.
• Natural hepatoprotective agents such as polyphenols, flavonoids, terpenoids, and alkaloids exert protective effects by activating the Nrf2/Keap1/ARE antioxidant pathway and inhibiting inflammatory signaling pathways like NF-κB and NLRP3 inflammasome.

Clinical Significance

Citation

Siddiqui Shakir, William Neha Ronald, Aggarwal Babita. Antimony- and NSAID-Induced Hepatotoxicity at the Molecular Crossroads: Redox, Inflammasome and Programmed Cell-Death Networks as Therapeutic Targets for Natural Hepatoprotective Agents. Journal of applied toxicology : JAT. 2026-Aug-16.