Protective effect of Ziziphus lotus fruit aqueous extract against zearalenone-induced immunotoxicity in mice under sub-chronic exposure

• ZEN raises p53, IL-6 and NF-κB, signaling severe liver injury. • ZLFE decrease p53 level, demonstrating an anti-apoptotic effect. • ZLFE decrease IL-6 and NF-κB levels, by which mitigate ZEN-inflammation. • ZEN depletes T cells and IgA/IgG; ZLFE restores immune balance. • Flavonoids and phenols in ZLFE exhibit an immunomodulatory effect. Zearalenone (ZEN), a mycotoxin produced by Fusarium species, is known for its toxic effects on multiple biological systems, including the liver and immune responses. This study aimed to investigate the protective role of Ziziphus lotus fruit extract (ZLFE) against ZEN-induced toxicity. Immunofluorescence analysis revealed significant overexpression of apoptotic markers, particularly p53, as well as pro-inflammatory IL-6 and NF-κB in hepatic tissue, in ZEN-treated groups, indicating severe hepatic damage and local liver inflammation. However, co-treatment with ZLFE markedly reduced these effects, demonstrating its anti-apoptotic and anti-inflammatory properties. Additionally, ZEN caused systemic immunosuppression evidenced by decreased inflammatory cytokine levels, as indicated by reduced levels of IFN-γ, TNF-α, IL-12, IL-6, and IL-1β in peripheral blood, while ZLFE supplementation significantly restored these cytokine levels toward control values. The study also confirmed ZEN's immunosuppressive effects, with a decrease in T-cell populations (CD4+, CD8+, CD54+, and CD56+) and immunoglobulin levels (IgA and IgG). Remarkably, ZLFE restored immune balance, mitigating the deleterious effects of ZEN. These findings suggest that ZLFE, rich in bioactive compounds like flavonoids and phenolic acids, can act as a natural protective agent against ZEN-induced apoptosis, hepatic inflammation, and immunosuppression.