Multifactorial mechanisms of 5-fluorouracil-induced cardiotoxicity and the cardioprotective role of gallic acid.

BACKGROUND: 5-Fluorouracil (5-FU) is an effective chemotherapeutic agent widely used in the treatment of solid tumors; however, its clinical use is limited by cardiotoxicity. This study investigated the molecular mechanisms underlying 5-FU-induced cardiotoxicity and evaluated the potential cardioprotective effects of gallic acid (GA). METHODS: Twenty-eight male Wistar albino rats were randomly assigned to four groups (n = 7/group): Control, GA, 5-FU, and 5-FU + GA. GA (120 mg/kg/day, orally) was administered for 7 consecutive days, and a single intraperitoneal dose of 5-FU (150 mg/kg) was given on day 5. Serum cardiac injury markers, cardiac oxidative stress parameters, inflammation-, ER stress-, autophagy-, and apoptosis-related gene expression, PI3K/AKT protein levels, and histopathological and immunohistochemical changes were evaluated. RESULTS: 5-FU significantly increased serum LDH and CK-MB levels, oxidative stress, inflammatory, ER stress, autophagy, and apoptosis-related markers, and induced marked histopathological and immunohistochemical alterations in cardiac tissue. Co-treatment with GA markedly ameliorated these biochemical, molecular, and histopathological changes, whereas GA alone produced findings comparable to those of the control group. CONCLUSIONS: GA protects against 5-FU-induced cardiotoxicity by attenuating oxidative stress, inflammation, ER stress, autophagy, and apoptosis, suggesting its potential as a cardioprotective adjunct during 5-FU chemotherapy.