Tannic Acid Suppresses Ferroptosis Induced by Iron Salophene Complex in Kidney Cells and Prevents Iron Overload-Induced Liver and Kidney Dysfunction in Rats.

Abstract

Iron toxicity intricately links with ferroptosis, a unique form of cell death, and is significantly influenced by lipid peroxidation. Despite its critical role in various diseases and drug development, the association between iron toxicity and ferroptosis remains relatively unexplored. Accidental iron ingestion has emerged as a growing concern, resulting in a spectrum of symptoms ranging from gastrointestinal discomfort to severe outcomes, including mortality. This research introduces tannic acid (TA), which contains numerous phenol groups, as a powerful antiferroptotic agent. In male Wistar rats, even a modest dose of TA (7.5 mg/kg) significantly curtailed thiobarbituric acid reactive substances (TBARS), a well-established indicator of lipid peroxidation, and mitigated iron accumulation induced by ferrous sulfate (FeSO₄) in the liver and kidney. The evidence supporting TA's protective function against iron-triggered liver and kidney dysfunction was substantiated by assessing specifically the levels of blood urea nitrogen (BUN) and alanine aminotransferase (ALT). In cell models using ferroptosis inducers such as iron-salophene (FeSP) and RAS-selective lethal 3 (RSL3), tannic acid (TA) exhibited superior protective capabilities compared to the traditional iron chelator, deferoxamine (DFO). Nrf2 and HO-1, regulators of antioxidant defense genes, are implicated in controlling ferroptosis. The expression of Nrf2 and HO-1 increased with TA treatment in the presence of FeSP, indicating their role in reducing lipid ROS levels. Additionally, TA significantly reduced the heightened levels of COX2, a marker associated with ferroptosis. In summary, the remarkable antiferroptosis activity of TA is likely due to its combined iron-chelating and antioxidant properties. With its safety profile for oral consumption, TA may offer benefits in cases of accidental iron ingestion and conditions like hemochromatosis.