Selenium nanoparticles confer protection against acetaminophen hepatotoxicity by attenuating oxidative stress, inflammation, and ferroptosis

Acetaminophen (APAP) overdose is a primary cause of acute drug-induced liver injury (AILI). Although N-acetylcysteine (NAC) serves as the established clinical antidote, its narrow therapeutic window underscores the critical need for more effective preventive and therapeutic strategies. Selenium nanoparticles (SeNPs), featuring high bioavailability and low toxicity, have emerged as promising agents for disease intervention. This study aimed to investigate the protective efficacy and mechanistic basis of biosynthesized SeNPs against APAP-induced AILI. Human normal hepatocyte (L-02) cells and an APAP-induced acute liver injury mouse model were employed. Hepatoprotective effects were assessed by cell viability, morphological observation, serum ALT/AST levels, histopathological examination, hepatic oxidative stress markers (GSH, T-SOD, MDA), inflammatory cytokine mRNA expression (IL-6, IL-1β, TNF-α, CCL5, CXCL2, CXCL10), GPX4 expression at mRNA and protein levels, and iron metabolism-related genes (TFRC, FTH1, FTL1, FPN, HMOX1) along with Fe²⁺ content and lipid peroxidation. SeNPs significantly alleviated APAP-induced cytotoxicity in L-02 cells, and in mice, they markedly mitigated hepatic necrosis and inflammatory infiltration, reduced serum ALT/AST, and normalized the liver index. Mechanistically, SeNPs enhanced antioxidant capacity (elevated GSH/T-SOD, reduced MDA), suppressed pro-inflammatory cytokine expression, reversed APAP-induced GPX4 downregulation, and regulated iron metabolism genes to diminish Fe²⁺ accumulation and lipid peroxidation, thereby inhibiting ferroptosis. SeNPs effectively protect against APAP-induced liver injury in vitro and in vivo by enhancing antioxidant defenses, suppressing inflammation, and modulating GPX4-mediated ferroptosis, offering a solid experimental basis for their development as a potential therapeutic agent against AILI.