Protective effect of pinocembrin on zearalenone-induced hepatotoxicity via PI3K/AKT and NRF2 signaling in albino mice

Background/aim: Zearalenone (ZEA) is a Fusarium-derived mycotoxin that frequently contaminates food and feed and induces hepatotoxicity in humans and animals through oxidative stress and inflammation. Pinocembrin (PCM), a naturally occurring flavonoid, has potent antioxidant and antiinflammatory properties. This study investigated the hepatoprotective effects of PCM against ZEA-induced liver injury in albino mice, with a focus on the nuclear factor erythroid 2-related factor 2 (NRF2) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathways. Materials and methods: Twenty-four albino male mice were allocated into four groups: (1) control (vehicle 0.05% dimethyl sulfoxide), (2) ZEA-treated (40 mg/kg body weight), (3) PCM-treated (50 mg/kg body weight), and (4) ZEA + PCM. After 42 days of oral treatment, serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were determined. Hepatic oxidative stress markers were assessed. Liver histopathology was evaluated using standard staining techniques. Western blot analysis was performed to determine the expression of several proinflammatory cytokines signaling proteins: interleukin-6, interleukin-1β, tumor necrosis factor-α, NRF2 pathway components, apoptosis-related proteins (B-cell lymphoma 2 [Bcl-2], cleaved caspase-3), and PI3K/Akt. Results: ZEA administration caused significantly elevated serum liver enzyme and hepatic malondialdehyde levels while causing a reduction in other oxidative stress markers. Histopathological examination revealed marked hepatic architectural disruption and cellular degeneration in the ZEA-treated group. Additionally, ZEA caused downregulation of antiapoptotic signaling proteins (such as Bcl-2) and upregulation of proinflammatory cytokines and cleaved caspase-3 expression. The coadministration of PCM facilitated markedly attenuated ZEA-induced biochemical, oxidative, inflammatory, apoptotic, and histopathological alterations. PCM treatment restored antioxidant enzyme activities and produced significant enhancement of NRF2/HO-1/NQO1 and PI3K/Akt signaling. Conclusion: PCM effectively protects against ZEA-induced hepatotoxicity in albino mice by mitigating oxidative stress, inflammation, and apoptosis. These protective effects are partially mediated through activation of the NRF2 signaling pathway and modulation of the PI3K/Akt pathway.