2. Academic Validation
  3. Environmental PFOS and 6:2 Cl-PFESA Reshape Ferroptosis Vulnerability in Liver Cancer

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

  • Environ Sci Technol. 2026 Mar 3;60(8):6096-6110. doi: 10.1021/acs.est.5c16490.
Jiawei Hong 1 2 3 4,  Keyi Du 1 4 5,  Tong Wu 1 4 5,  Zhuoyi Wang 2 3,  Jiamian Fang 1 4 5,  Siqi Zhang 1 4 5,  Weichen Zhang 1 4 5,  Yifan Jiang 1 4 5,  Hanxi Yu 4 5,  Tingting Pan 4 5,  Minjie Zhu 6,  Shusen Zheng 1 2 3 4 5,  Hangbiao Jin 7 8,  Yuanchen Chen 7 8,  Linping Cao 1 4 5
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310022, China.
  • 3 Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, China.
  • 4 NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang University, Hangzhou 310003, China.
  • 5 Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310003, China.
  • 6 Department of General Surgery, Hangzhou Third People's Hospital, Hangzhou, Zhejiang 310000, China.
  • 7 State Key Laboratory of Green Chemical Synthesis and Conversion, Zhejiang Key Laboratory of Clean Energy Conversion and Utilization, Science and Education Integration College of Energy and Carbon Neutralization, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China.
  • 8 Innovation Research Center of Advanced Environmental Technology, Eco-Industrial Innovation Institute ZJUT, Quzhou, Zhejiang 324400, China.
PMID: 41700700 DOI: 10.1021/acs.est.5c16490
Abstract

Ferroptosis, an iron-driven form of programmed cell death characterized by lipid peroxidation and Reactive Oxygen Species (ROS) accumulation, is essential for tissue homeostasis and tumor suppression, yet its regulation in hepatocellular carcinoma (HCC) under environmental pollutant exposure remains unclear. Here, using long-term in vitro and in vivo exposure models with environmentally relevant doses combined with multiomics analyses, we show that per- and polyfluoroalkyl substances (PFAS) exert antithetical effects in HCC and normal hepatocytes. Whereas PFAS promote Ferroptosis in normal cells, chronic exposure to perfluorooctanesulfonate (PFOS) and its replacement 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) markedly enhances Ferroptosis resistance in HCC. Mechanistically, these contaminants bind to and activate STAT3, which transcriptionally upregulates GPX4, establishing a STAT3-GPX4 self-activating loop that suppresses lipid peroxidation and protects tumor cells from ferroptotic death. Notably, 6:2 Cl-PFESA shows stronger activity than PFOS, challenging its designation as a safer substitute. Our findings reveal a striking cell type-specific duality of PFAS action─inducing Ferroptosis in normal hepatocytes but enabling evasion in HCC through signaling reprogramming. This dichotomy advances understanding of pollutant-cancer interactions, highlights the STAT3-GPX4 axis as a therapeutic vulnerability, and underscores the health risks posed by PFAS replacements.

Keywords

HCC; STAT3-GPX4; cell-type duality; ferroptosis resistance; pfass.

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