A protective trend of N-acetylcysteine against aluminum-induced hepatotoxicity in rats involving the Nrf2/HO-1 and NF-κB pathways

Aluminum (Al), the most abundant metal in the Earth's crust, can enter organisms through multiple pathways, and its accumulation has been confirmed to induce hepatic injury. As an antioxidant, N-acetylcysteine (NAC) has been validated for decades for its ability to counteract oxidative stress; however, the molecular mechanisms by which it alleviates Al‑induced hepatotoxicity remain unclear. For the in vivo study, 32 rats were randomly divided into four groups of equal size (n = 8): control, Al, Al + NAC, and NAC. The control group received an equivalent volume of normal saline. The Al group received AlCl₃ (10 mg/kg/day, i.p.). The NAC group received NAC (100 mg/kg/day, i.p.). The Al + NAC group received both AlCl₃ (10 mg/kg/day) and NAC (100 mg/kg/day). After 28 days, serum biochemical parameters, liver histopathological changes, oxidative stress markers, apoptosis-related proteins levels, and key proteins in the Nrf2/HO-1 and NF-κB pathways were examined. For in vitro validation, the normal rat liver cell line (BRL3A) was used to further elucidate the effects of Al exposure on liver damage and the antagonistic effects of NAC. Our results showed that Al exposure induced oxidative stress, apoptosis, and activation of the Nrf2/HO-1 and NF-κB pathways in hepatocytes. NAC co-treatment significantly reduced ROS and MDA levels, restored SOD activity and mitochondrial membrane potential, and decreased apoptosis in BRL3A cells. It also suppressed Al‑induced activation of the Nrf2/HO-1 and NF-κB pathways and reduced the nuclear translocation of Nrf2 and p65. In vivo, NAC also exhibited a beneficial protective trend in biochemical and histopathological parameters and effectively modulated the Nrf2/HO-1 and NF-κB pathways at the molecular level. In conclusion, NAC effectively scavenges reactive oxygen species, inhibits NF-κB activation, and modulates the Nrf2 pathway, thereby exerting antioxidant and anti‑inflammatory effects and demonstrating protective potential against Al‑induced hepatotoxicity.