# Impact of PFAS exposure on lipid metabolic pathways: mechanisms and implications in carcinogenesis

## TL;DR

This review explores how PFAS chemicals disrupt lipid metabolism, potentially leading to cancer by altering key metabolic pathways and promoting tumor growth.

## Contribution

The paper synthesizes current evidence to highlight lipid metabolism as a novel mechanistic link between PFAS exposure and carcinogenesis.

## Key findings

- PFAS exposure is associated with increased blood lipid levels and dysregulation of lipid-related transcription factors.
- Disruption of lipid metabolism by PFAS can lead to abnormal lipid accumulation and activation of pro-oncogenic pathways.
- Structural similarities between PFAS and fatty acids allow them to interfere with lipid transport and nuclear receptor activation.

## Abstract

Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic chemicals widely used in industrial and consumer products owing to their unique surfactant properties. Their environmental persistence and bioaccumulative nature have resulted in widespread contamination of water, soil, and food sources, raising significant concerns for human health. Epidemiological and toxicological studies increasingly associate PFAS exposure with elevated risks of cancers, including liver, kidney, breast, and testicular cancers; however, the mechanisms underlying these associations remain incompletely understood. One emerging explanation is that PFAS disrupt lipid metabolism, a pathway frequently reprogrammed during cancer initiation and progression. PFAS share structural similarities with endogenous fatty acids and can bind to lipid transport proteins and/or activate lipid-sensitive nuclear receptors. Current evidence indicates that PFAS exposure is associated with increased blood lipid levels, as well as dysregulation of key transcription factors—such as peroxisome proliferator-activated receptors and sterol regulatory element-binding proteins—that can link PFAS exposure to tumor-promoting metabolic alterations. These disruptions can impair dietary fatty acid uptake and de novo lipid synthesis, leading to abnormal lipid accumulation, oxidative stress, and activation of pro-oncogenic signaling pathways. The purpose of this review is to synthesize current evidence on how PFAS exposure contributes to carcinogenesis through the disruption of lipid metabolism. By integrating findings from population studies, mechanistic research, and molecular insights, this review highlights lipid dysregulation as a critical connection between PFAS exposure and cancer biology and underscores the need for deeper investigation into this pathway.