Boron Triggers Hepatic Ferroptosis: Unveiling the Dual-Pathogenic Nexus of Oxidative Stress and SLC7A11/GPX4 Dysregulation

Boron compounds, classified as prohibited food additives due to their high toxicity, persist in pesticides and fertilisers, industrial processes, food supply chains, and consumer goods, perpetuating multisource exposure risks. Chronic ingestion may induce fatal hepatorenal injury; however, mechanistic insights and epidemiological surveillance remain critically lacking amidst sector-wide regulatory gaps. This study employed integrated cellular and organismal models to elucidate the relationship between boron-induced hepatotoxicity and ferroptosis. We demonstrate that dietary boron accumulation in chicken livers is associated with histopathological damage, mitochondrial cristae dissolution and atrophy (a hallmark of ferroptosis), and elevated serum biomarkers AST and ALT. Boron exacerbates oxidative damage in hepatocytes by elevating malondialdehyde (MDA) production while modulating the Nrf2/ARE antioxidant signaling pathway—specifically downregulating key genes (Nrf2, HO-1, GCLM, CAT). Concurrently, it inhibits critical antioxidant enzymes (SOD, T-AOC), thereby depleting cellular antioxidant defenses. Crucially, boron disrupts iron homeostasis and induces ferroptosis by dysregulating the SLC7A11-GPX4 pathway: upregulating pro-ferroptotic genes (ACSL4, TF, TFR) and downregulating cytoprotective genes (SLC7A11, GPX4, FTH1). Co-treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated boron-induced oxidative damage, whereas the ferroptosis inducer Erastin potentiated toxicity. Collectively, we pioneer the dual-pathogenic mechanism of boron hepatotoxicity—oxidative stress and ferroptotic cell death—establishing the SLC7A11/GPX4 axis as a novel therapeutic target against boron toxicity.