# Pesticides Drive Liver Diseases Through Non-Apoptotic Regulated Cell Death Pathways

## TL;DR

Pesticides contribute to liver diseases by triggering non-apoptotic cell death pathways like ferroptosis and necroptosis, leading to inflammation and tissue damage.

## Contribution

This review highlights the novel role of non-apoptotic regulated cell death pathways in pesticide-induced liver toxicity.

## Key findings

- Pesticides induce non-apoptotic regulated cell death pathways such as ferroptosis, necroptosis, and pyroptosis in liver cells.
- These cell death mechanisms contribute to liver steatosis, fibrosis, and inflammation through pro-inflammatory cytokine production.

## Abstract

A compelling body of evidence links pesticide exposure to human diseases. The liver plays a central role in the detoxification of pesticides, suggesting intense pesticide–liver cell interactions. A growing body of studies highlighted in this review supports the contribution of pesticides of various chemical classes to the development of non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), liver cirrhosis, viral hepatitis, hepatocellular carcinoma, etc., via disrupting lipid and carbohydrate metabolism and redox homeostasis, promoting endoplasmic reticulum stress and mitochondrial dysfunction, as well as stimulating apoptosis, fibrosis, and inflammation. In this review, we systematically illustrated an underappreciated mechanism of pesticide-induced overall and hepatic toxicity, i.e., the ability to induce non-apoptotic regulated cell death (RCD) pathways such as ferroptosis, necroptosis, and pyroptosis. Our analysis indicates that pesticides are implicated in driving liver diseases by inducing ferroptosis, necroptosis, and pyroptosis. Non-apoptotic RCDs mediate pesticide-induced liver steatosis and fibrosis. Furthermore, these cell death modalities fuel inflammation through the promotion of pro-inflammatory cytokine production and the generation of damage-associated molecular patterns. Understanding of deeper mechanisms of pesticide-induced effects on the non-apoptotic cell death machinery and subsequent immunogenic effects in liver pathology might help develop novel preventive strategies to reduce liver damage.