Unfolding protection: Terminalia arjuna targets UPR pathways to counteract ER stress in hepatotoxicity

Background: Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation. Objective: This study assesses Terminalia arjuna bark extract (TAE) against APAP-induced toxicity in rats, comparing its efficacy with N-acetylcysteine (NAC) through key signaling and inflammatory markers. Methods: Twenty-four Wistar rats were equally divided into four groups: Control Negative (CN, no treatment), Control Positive (CP, acetaminophen 350?mg/kg), N-acetylcysteine (NAC, 150?mg/kg), and Terminalia arjuna bark extract (TAE, ethanolic, 80?mg/kg). Over 14 days, liver injury was induced in the CP group via acetaminophen, while the NAC and TAE groups received their respective treatments. Animals were decapitated on day 15, and biological samples were collected for analysis. Biochemical assessments included liver function markers (ALT, AST) and oxidative stress parameters (SOD, TAC, TBARS, TOS). Gene expression studies were performed for oxidative stress regulators (Keap1, Nrf2) and ER stress signaling molecules (ERK, JNK, PPAR-?, AKT). Histopathological examination evaluated liver architecture and cellular integrity. Results: Acetaminophen induced significant hepatotoxicity, as reflected by elevated liver enzymes, increased oxidative stress, altered gene expression, and disrupted liver histology. APAP toxicity resulted in elevated oxidative stress, apoptosis, inflammation, and ER stress, leading to significant hepatic damage (p < 0.0001 vs CN). NAC and TAE treatments mitigated these effects, with TAE demonstrating superior improvement in oxidative stress markers (p < 0.0001 vs CP). Gene expression analysis revealed a protective shift in the Keap1-Nrf2 pathways in the treated groups. Histopathology confirmed reduced necrosis and preserved hepatic architecture in the NAC and TAE groups. Conclusion: T. arjuna exhibits potent hepatoprotective effects, comparable to NAC, through modulation of oxidative stress, apoptosis, and ER stress pathways. Further studies are needed to explore its clinical applicability in acute liver injury management.