# Integrated Network Toxicology and Transcriptomics Reveal Molecular Mechanisms of Cadmium-Exposed Liver Injury in Swine

## TL;DR

The study shows how long-term cadmium exposure harms pig liver cells and identifies key molecular pathways that could help monitor and prevent such damage in livestock.

## Contribution

The study integrates multi-omics data to reveal the PI3K-Akt signaling pathway as a central driver of cadmium-induced liver injury in pigs.

## Key findings

- Cadmium exposure caused liver cell swelling, fatty changes, and mitochondrial dysfunction in piglets.
- Transcriptomic analysis identified 1092 differentially expressed genes linked to cadmium toxicity.
- The PI3K-Akt signaling pathway was identified as a central mechanism in cadmium-induced liver injury.

## Abstract

Cadmium is a toxic metal that can enter livestock through contaminated soil, water, or feed, raising food-safety concerns. We aimed to explain how long-term cadmium exposure damages pig liver and to find early warning signals for monitoring. We fed piglets a cadmium-containing diet for 40 days and evaluated liver injury using histopathology, ultrastructural imaging, and transcriptomic profiling. Cadmium exposure disrupted normal liver structure, caused swollen and fatty liver cells, damaged the cell’s energy-producing structures, and increased the cell’s recycling process. The blood marker of liver injury increased, and more than one thousand genes changed their activity. By combining gene results with computer analysis, we identified a central control system that coordinates cell survival, energy use, and stress responses as a key driver of cadmium-related liver injury. These results help explain why cadmium-contaminated environments can threaten the safety of animal products and provide practical molecular markers that may improve monitoring and prevention in pig production chains.

Cadmium (Cd) is an environmental toxicant that poses significant risks to food safety and public health through its bioaccumulation in the food chain. The liver is a primary target for chronic Cd toxicity, yet the system-level mechanisms, particularly in physiologically relevant swine models, remain incompletely understood. This study employed an integrated multi-omics approach to elucidate the mechanisms of Cd-exposed hepatotoxicity in weaned piglets. We combined histopathological examination, transmission electron microscopy, and transcriptome sequencing. Our results revealed severe hepatic damage, characterized by disorganized architecture, vacuolar degeneration, mitochondrial dysfunction, and autophagic activation. Network toxicology predicted 3727 potential targets of Cd-exposed liver injury, while transcriptomics identified 1092 differentially expressed genes (DEGs). Crucially, the convergent analysis of both datasets demonstrated that the PI3K-Akt signaling pathway was the central hub, pinpointing it as a pivotal mechanism in Cd-driven hepatotoxicity. Functional enrichment analyses further highlighted dysregulation in immune-inflammatory responses, lipid metabolism, and oxidative stress. Our findings provide a comprehensive systems-level perspective on chronic Cd hepatotoxicity in a translational swine model. We propose the PI3K-Akt pathway and other identified core targets (EGFR, histones, ribosomal proteins) as critical biomarkers for monitoring Cd contamination in swine production chains, offering valuable insights for environmental risk assessment and agricultural product safety.