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Abstract

Silymarin, a polyphenolic flavonolignan complex extracted from Silybum marianum, is well recognized for its hepatoprotective, nephroprotective, and immunomodulatory potential through free radical scavenging and membrane-stabilizing actions. Betaine, a naturally occurring methyl donor and osmoprotectant, contributes to maintaining cellular osmotic equilibrium, reducing oxidative stress, and modulating inflammatory cascades. Despite their individual therapeutic merits, limited data exist on their combined or nanoformulated application in avian oxidative pathophysiology. The present study, therefore, explores the synergistic efficacy of betaine and silymarin in comparison to a silymarin-based nanocomposite (CME@ZIF-8) against carbon tetrachloride (CCl₄) induced oxidative damage in the kidneys, thymus, and blood of broiler chicks. A total of 120 healthy broiler chicks were randomly divided into eight experimental groups, including control, CCl₄-treated, and treatment groups receiving graded doses of silymarin (0.5, 1.0, and 1.5 mg/kg body weight), its nanoformulation CME@ZIF-8, betaine alone, and a combined betaine–nanosilymarin regimen. Oxidative stress and tissue integrity were evaluated through biochemical markers such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), alongside histopathological assessment of renal and thymic tissues. The results demonstrated that silymarin treatment effectively mitigated CCl₄-induced oxidative insults in a dose-dependent manner, with pronounced reductions in lipid peroxidation and restoration of enzymatic antioxidant activity. The nanoformulated silymarin (CME@ZIF-8) significantly enhanced bioavailability and intracellular retention, resulting in superior nephroprotective and thymoprotective outcomes. Remarkably, co-administration of betaine with nanosilymarin produced the most comprehensive recovery profile, characterized by improved weight gain, normalized hematological parameters, enhanced tissue architecture, and robust antioxidant enzyme activity. This synergistic efficacy can be attributed to the complementary mechanisms of action of betaine and silymarin where betaine’s osmoprotective and methyl-donating roles stabilize cellular metabolism, while nanosilymarin’s enhanced free-radical scavenging capacity and targeted delivery optimize antioxidant responses. Collectively, these findings establish the betaine–nanosilymarin combination as a potent and sustainable therapeutic alternative to synthetic antioxidants for alleviating oxidative stress and improving immune competence in poultry.