Caffeic Acid–Biogenic Amine Complexes Outperform Standard Drugs in Reducing Toxicity: Insights from In Vivo Iron Chelation Studies

Iron homeostasis imbalance, caused by conditions such as thalassemia, sickle cell anemia, and myocardial infarction, often results in elevated free iron levels, leading to ferroptosis and severe organ damage. While current iron chelators like deferoxamine (DFO) and deferiprone are effective, they are associated with significant side effects, including nephrotoxicity, gastrointestinal bleeding, and liver fibrosis. This creates an urgent need for safer, natural-product-based alternatives for effective iron chelation therapy (ICT). This study investigates caffeic acid (CA)-based complexes with biogenic amines, specifically spermine (CA-Sp) and histidine (CA-His), as potential ICT candidates. Initial in vitro assays on HEK-293 cells under iron dextran (ID)-induced toxicity have demonstrated their protective effects, with CA-Sp exhibiting superior efficacy. The in vivo studies in mice have further validated their potential, showing remarkable iron chelation and toxicity mitigation compared to DFO. Inductively coupled plasma mass spectrometry (ICP-MS) reveals significant iron excretion in fecal matter in the treatment group along with reductions in serum ferritin levels. The markers of nephrotoxicity (creatinine) and liver function (ALT, AST) have also been shown to be normalized in treated groups, while immunological analyses have revealed restored levels of neutrophils, T cells, and B cells. Additionally, the inflammatory cytokines, TNF-α and IL-6, have exhibited significant reductions, with the CA-based formulations surpassing the effects of DFO. Histological analyses using Prussian blue staining have further confirmed reduced iron deposition in vital organs such as the liver, kidney, and spleen. These findings highlight CA-Sp as a particularly promising candidate for ICT, offering a safer and more effective strategy for managing iron overload and its associated complications.