Targeting NF-κB/TLR4/ERK/MYD88 and Caspase-1/IL-1β Pathways by Diacerein in Alleviation of 5-Fluorouracil-Induced Myocardial, Corneal, and Retinal Injury

Chemotherapeutic agents, including 5-fluorouracil (5-FU), are widely used to treat various types of malignant disorders, but cardiac injury limits their clinical benefit. Thus, we aimed to evaluate the usefulness of diacerein (DIA) in alleviating 5-FU myocardial and ocular injury. 50 male Wistar rats were included in the current model, and 5-FU was administered as a single intraperitoneal dose (150 mg/kg) on the first day of the study to induce myocardial and ocular injury, followed by co-administration of DIA (25, 50 mg/kg/day) by oral gavage for 7 days. 5-FU-induced myocardial and ocular injury was detected as structural changes in cardiac, corneal, and retinal tissues, with significant increases in the cardiac injury biomarkers, toll-like receptor 4 (TLR4), extracellular signal-regulated kinase (ERK), total oxidant status (TOS), oxidative stress index (OSI), nuclear factor kappa b (NF-κB), interleukin 1β (IL-1β), caspase-3, and caspase-1 expressions. Conversely, there were marked decreases in the serum total antioxidant capacity (TAC) and toxic features in the histopathological evaluation. However, co-administration of DIA ameliorated 5-FU-induced toxic effects and improved biochemical and structural changes. This beneficial effect of DIA is attributed to its ability to modulate the NF-κB/TLR4/ERK/caspase-1/IL-1β pathway, suppressing apoptosis and oxidative stress. DIA may be a future adjuvant medical therapy to reduce 5-FU side effects.