Effect of the Nrf2/HO-1 pathway on aluminum-induced liver injury

Chronic exposure to aluminum (Al) can lead to the accumulation of Al in the liver, which negatively impacts liver structure and function. Oxidative stress is extensively identified as a key contributor to Al toxicity. The Nrf2/HO-1 pathway maintains cellular redox homeostasis and protects from oxidative stress through its antioxidative and cytoprotective role. However, its role in Al-induced liver damage remains unclear. In this study, rats were grouped into the control (C), Al exposure (Al), Al exposure + Omaveloxolone (Al+O), and Al exposure + ML385 (Al+M) groups, and their liver function, hepatic Al content, histopathological changes in liver tissue, and hepatocyte apoptosis were assessed. The Nrf2/HO-1 signaling- and apoptosis-associated protein levels were evaluated using Western blotting. In vitro, with BRL3A cells as a model, Al exposure's influence in cell viability, MMP, and Nrf2/HO-1- and apoptosis-associated protein levels was assessed. The Nrf2/HO-1 pathway was also modulated to investigate changes in oxidative stress and apoptosis-related markers following intervention. The results showed that Al accumulation in liver tissue led to rat histopathological changes and liver dysfunction, promoting oxidative stress and hepatocyte apoptosis, while also enhancing Nrf2/HO-1-associated protein levels. Similar findings were observed in in-vitro experiments. Furthermore, the Nrf2/HO-1 signaling activation mitigated Al-triggered oxidative stress and apoptosis, whereas its inhibition reduced these protective effects. This study indicated that Al exposure could induce s oxidative damage in rat livers and BRL3A cells; activation of the Nrf2/HO-1 pathway serves as a critical compensatory mechanism against Al toxicity, but its protective efficacy is limited.