α-Lipoic Acid Alleviated Fluoride-Induced Hepatocyte Injury via Inhibiting Ferroptosis

Abstract

Fluoride is widely used in agricultural production and food packaging. Excessive fluoride in water and food is a serious threat to liver health. α-Lipoic acid, a natural free radical scavenger, has hepatoprotective properties. However, the protective effect of α-lipoic acid on fluorohepatotoxicity is uncertain. The aim of this study was to investigate the mechanism of ferroptosis in α-lipoic acid preventing fluoride-induced hepatotoxicity. Five-week-old ICR mice were treated with sodium fluoride (100 mg/L) and/or α-lipoic acid (200 mg/kg) for 9 weeks. The results showed that α-lipoic acid attenuated fluoride-induced damage to liver morphology and ultrastructure. Moreover, α-lipoic acid alleviated fluoride-induced iron accumulation, increased oxidative stress, and elevated lipid peroxidation in the liver. In addition, the mechanism study found that α-lipoic acid prevented fluoride-induced ferroptosis through the System Xc–/GPX4 axis, lipid peroxidation axis, and iron metabolism axis, but it was interestingly not regulated by mitochondrial free radical axis in the hepatocytes. Altogether, this study indicated that α-lipoic acid prevents fluoride-induced liver injury by inhibiting ferroptosis, which has potential implications for the prevention and treatment of fluoride-induced liver injury.

The Role of Alpha Lipoic Acid and Tempol Against Liver Injury after Acetaminophen Subacute Exposure in Mice

“…This underscores the potential of lipoic acid to be employed as an effective therapeutic agent for treating APAP overdose-induced liver damage. Also, a certain study that is in agreement with histopathological findings in the current study, has found that results of the study indicate that it can mitigate the harm to the liver morphology and ultrastructure induced by hepatotoxicity caused by fluoride (Zhao et al, 2022). In a scientific investigation involving rodents that had sustained liver damage due to lipopolysaccharide injection, it was discovered that lipoic acid served to regulate the equilibrium of the oxidant/antioxidant status and avert the occurrence of oxidative stress (Cimen et al, 2019;Zalzala and Kareem, 2021;Al-Azzawi and Baraaj, 2016).…”

“…Furthermore, it was observed that Tempol treatment led to a decrease in the expression of pro-apoptotic proteins (cleaved caspase-3 and Bax) and an increase in the expression of the anti-apoptotic protein Bcl-2 in the liver. Moreover, the number of apoptotic cells, as determined by TUNEL staining, was significantly reduced following Tempol treatment, suggesting its potential to prevent apoptosis (Zhao et al, 2022). Overall, the evidence suggests that Tempol has the ability to restore normal liver function in mice with APAP-induced acute hepatotoxicity by activating the PI3K/Akt/Nrf2 pathway, thereby enhancing the antioxidant response and inhibiting hepatic apoptosis.…”

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…Alpha lipoic acid is an important natural free radical scavenger. It was reported to inhibit the occurrence of lipid peroxidation via the System Xc - /GPX4 axis, thereby preventing fluorine-induced ferroptosis in liver cells [ 129 ]. Alpha lipoic acid also ameliorated cobalt-induced liver injury via inhibiting ferroptosis [ 130 ].…”