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

## TL;DR

This study shows that high boron intake harms chicken livers by causing oxidative stress and a type of cell death called ferroptosis.

## Contribution

The paper identifies the SLC7A11/GPX4 pathway as a novel target for mitigating boron-induced liver toxicity.

## Key findings

- Boron causes liver damage in chickens through oxidative stress and ferroptosis.
- Boron disrupts the SLC7A11/GPX4 pathway, leading to ferroptotic cell death.
- Ferroptosis inhibitors reduce boron-induced liver toxicity in chickens.

## Abstract

Boron is essential in trace amounts but toxic in excess. Chickens in farming may ingest high boron from water or feed, yet how it damages the liver is unclear. This study examined whether boron causes liver injury through ferroptosis. We found that boron-fed chickens showed liver damage, oxidative stress, and disrupted iron balance. Boron triggered ferroptosis by blocking a key cellular defense pathway (SLC7A11/GPX4). These results first explain how boron harms the liver, offering a scientific basis to reduce its risk in poultry farming.

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.