Environmental PFOS and 6:2 Cl-PFESA Reshape Ferroptosis Vulnerability in Liver Cancer

Area of Science:

• Environmental Toxicology
• Cancer Biology
• Cell Death Research

Background:

• Ferroptosis, a cell death pathway involving iron and lipid peroxidation, is crucial for health and cancer suppression.
• The impact of environmental pollutants like PFAS on ferroptosis in liver cancer is not well understood.

Purpose of the Study:

• To investigate the effects of PFAS on ferroptosis in hepatocellular carcinoma (HCC) and normal hepatocytes.
• To elucidate the underlying molecular mechanisms of PFAS-induced ferroptosis modulation in HCC.

Main Methods:

• Utilized long-term in vitro and in vivo exposure models with environmentally relevant doses of PFAS.
• Employed multiomics analyses to understand the molecular responses.
• Investigated the role of the STAT3-GPX4 signaling axis.

Main Results:

• PFAS promote ferroptosis in normal hepatocytes but induce resistance in HCC.
• Chronic exposure to PFOS and 6:2 Cl-PFESA enhances ferroptosis resistance in HCC.
• PFAS activate STAT3, upregulating GPX4 and creating a self-sustaining loop that suppresses lipid peroxidation and ferroptosis in HCC.
• 6:2 Cl-PFESA demonstrated stronger effects than PFOS, questioning its safety.

Conclusions:

• PFAS exhibit a dual effect: inducing ferroptosis in normal cells while promoting resistance in HCC via STAT3-GPX4 pathway reprogramming.
• This highlights potential health risks associated with PFAS and their replacements.
• The STAT3-GPX4 axis represents a potential therapeutic target for HCC.