Gallic acid protects the heart from chemotherapy drug 5-fluorouracil toxicity

In a finding that could reshape how oncologists protect the heart during some of the most widely used chemotherapy in the world, a team of researchers in Türkiye has reported that gallic acid, a simple plant-derived polyphenol, shields heart tissue from the multi-layered damage inflicted by 5-fluorouracil. The new study, published in Molecular Biology Reports, provides one of the most comprehensive molecular portraits to date of how this chemotherapy agent injures the myocardium, and demonstrates through a carefully controlled animal experiment that a single natural compound can intervene on nearly every pathological pathway the drug activates.

5-Fluorouracil, commonly abbreviated 5-FU, has been a cornerstone of treatment for solid tumors, particularly colorectal cancer, for more than six decades. Its clinical value is beyond dispute, yet cardiologists and oncologists have long wrestled with a troubling side effect profile that ranges from chest pain and arrhythmias to myocarditis, coronary vasospasm, and in severe cases sudden cardiac death. Unlike the well-characterized cardiotoxicity of anthracyclines, which accumulates with cumulative dosing, 5-FU cardiac injury can appear abruptly and unpredictably, sometimes during the very first infusion. The exact mechanisms have remained frustratingly murky, and this uncertainty has hampered efforts to develop rational protective strategies for patients.

The research team, led by Gürkan Imre of Lokman Hekim Van Hospital and Cuneyt Caglayan of Bitlis Eren University, with senior author Fatih Mehmet Kandemir of Aksaray University, set out to map those mechanisms systematically and then test whether gallic acid could blunt them. Their experimental design was straightforward but rigorous. Twenty-eight male Wistar albino rats were randomly divided into four equal groups of seven animals each. One group served as untreated controls. A second received only gallic acid at a dose of 120 milligrams per kilogram per day, administered orally for seven consecutive days. A third group received a single intraperitoneal injection of 5-fluorouracil at 150 milligrams per kilogram on the fifth day of the protocol, a dose known to provoke acute cardiac injury in this species. The fourth group received both treatments, allowing the investigators to observe what happened when the protective compound was already present in the circulation when the chemotherapy strike occurred.

The scale of injury produced by 5-FU alone was striking. Within the cardiac tissue, the researchers documented a cascade of damage spanning five interlocking domains: oxidative stress, inflammation, endoplasmic reticulum stress, dysregulated autophagy, and apoptosis, the programmed cell death pathway. Serum biomarkers told the first part of the story. Lactate dehydrogenase and creatine kinase-MB, enzymes that leak into the bloodstream when heart muscle cells are damaged, rose significantly in the 5-FU group, providing biochemical confirmation that the drug had breached cardiomyocyte membranes and disrupted cellular energetics.

Beneath those circulating markers, the molecular machinery of the heart was in open revolt. Oxidative stress parameters revealed that 5-FU had tipped the delicate redox balance of the myocardium, overwhelming the tissue with reactive oxygen species while depleting its antioxidant defenses. This matters because cardiomyocytes are extraordinarily mitochondria-rich cells, dependent on a continuous, tightly controlled flow of electrons through the respiratory chain, and they are therefore exquisitely vulnerable to oxidant attack. When lipid peroxidation and protein damage accumulate faster than repair systems can cope, cell membranes fail, mitochondrial permeability transitions occur, and the cell begins its slide toward death. The inflammatory arm of the response compounded this injury, with pro-inflammatory gene expression climbing markedly, a pattern consistent with the growing recognition that chemo-induced cardiac injury shares mechanistic features with sterile inflammatory diseases of the heart.

Perhaps the most technically interesting portions of the study concern the endoplasmic reticulum and autophagy pathways, which have only recently been implicated in 5-FU cardiotoxicity. The endoplasmic reticulum is the cellular factory where proteins are folded and quality-checked, and when it is stressed, it initiates the unfolded protein response, which can either restore homeostasis or, if the stress persists, trigger cell death. The researchers found that 5-FU significantly upregulated ER stress-related markers in cardiac tissue, and they linked this to dysregulated autophagy, the cellular housekeeping process by which damaged organelles and proteins are degraded and recycled. Autophagy under ER stress has a well-documented dual personality: at moderate levels it is protective, clearing away debris, but when excessive or misdirected it becomes an executioner that dismantles the cell from within. The 5-FU group showed the pathological face of this process, with autophagy-related genes rising in concert with apoptosis markers, suggesting that the chemotherapy had pushed cardiomyocytes past the point where self-digestion could save them and into self-destruction.

Against this backdrop of multi-system damage, gallic acid’s performance was remarkable. In the combined treatment group, co-administration of the polyphenol markedly ameliorated virtually every parameter the team measured. Serum LDH and CK-MB, the blood signatures of cardiac injury, were pulled back toward baseline. Oxidative stress markers fell as the antioxidant capacity of the tissue recovered. Inflammatory gene expression was damped. ER stress and the runaway autophagy it provokes were attenuated. Apoptosis-related markers, which had surged in the 5-FU-only animals, subsided. Histopathological examination of heart sections, in which trained eyes assess the physical architecture of the myocardium, confirmed that the tissue-level devastation seen with 5-FU alone was substantially reduced when gallic acid was on board. Immunohistochemical staining, which visualizes the spatial distribution of specific proteins within the tissue, corroborated these findings at the cellular scale. Importantly, rats that received gallic acid alone looked essentially identical to untreated controls on every measure, indicating that the compound was not merely shifting one form of toxicity into another.

The authors also probed the PI3K/AKT signaling axis, a survival pathway whose protein levels were assessed in the cardiac tissue. This pathway has emerged in recent years as a central node in cardioprotection, with a growing literature showing that natural compounds against cytotoxic drug-induced cardiac injury often converge on it. The context matters here because the relationship between AKT signaling and 5-FU is nuanced: in cancer cells, over-activation of AKT can drive resistance to the drug, but in the heart, maintaining AKT-mediated survival signaling appears to be protective. The study’s findings on this pathway situate gallic acid within a broader pharmacological strategy in which cardioprotective adjuncts preserve the heart’s pro-survival wiring while the chemotherapy performs its cytotoxic work against the tumor.

Gallic acid itself is a small phenolic acid found abundantly in gallnuts, grapes, tea leaves, oak bark, and many fruits and vegetables. It has attracted scientific attention for its antioxidant, anti-inflammatory, and cytoprotective properties, and previous animal work from some of the same collaborators showed protective effects against doxorubicin-induced cardiotoxicity, another notorious form of chemo-related heart damage. Earlier studies have also documented its benefit in isoproterenol-induced cardiac injury and in cisplatin-treated cardiomyocytes. What distinguishes the new work is the breadth of the mechanistic interrogation. Rather than measuring one or two endpoints, the team assembled a systems-level picture spanning gene expression, protein signaling, serum biochemistry, tissue morphology, and protein localization, all within a single experimental framework.

The clinical implications, while tantalizing, come with necessary caveats. This was an animal study using a single high dose of 5-FU in a rodent model, and the dose of gallic acid and the timing of administration were optimized for the experiment rather than for human oncology practice. Translating these results into patients will require pharmacokinetic studies, safety trials, and demonstrations that the polyphenol does not interfere with the anti-tumor efficacy of the chemotherapy, a question of paramount importance given that some antioxidant compounds have shown the capacity to protect cancer cells as well as healthy ones. The researchers themselves framed gallic acid as a potential cardioprotective adjunct during 5-FU chemotherapy, a formulation that leaves the crucial oncological questions open to future work.

Even so, the study arrives at a moment of genuine unmet need. As colorectal cancer treatment regimens increasingly incorporate fluoropyrimidines like 5-FU and its oral prodrug capecitabine, the population exposed to their cardiac risks continues to grow, and cardiologists have few validated tools for prevention. Other candidate protectors, from N-acetylcysteine and empagliflozin to thymoquinone, quercetin, naringin, and myricetin, have each shown promise in preclinical models by targeting overlapping but incomplete slices of the injury cascade. The Turkish team’s contribution is to show that gallic acid engages the full pentad of pathological mechanisms, oxidative stress, inflammation, ER stress, autophagy, and apoptosis, simultaneously, which may explain the striking coherence of its protective effect across biochemical, molecular, and histological readouts.

All experimental procedures in the study were reviewed and approved by the Animal Experiments Ethics Committee of Necmettin Erbakan University in Konya, Türkiye, under approval number 2025-69, and the authors declared no competing interests. The work was conducted without dedicated external funding. As the search for cardio-oncology solutions accelerates, this study adds a compelling candidate to the pipeline, one whose molecular reach across five distinct injury pathways suggests that the humble gallic acid molecule may deserve a far larger role in protecting the hearts of patients fighting cancer.