Water-insoluble components of PM2.5 are major triggers of pulmonary ferroptosis by inducing mitochondrial damage via Nrf2/Prdx6 pathway

  • Ecotoxicol Environ Saf. 2026 Aug:321:120359. doi: 10.1016/j.ecoenv.2026.120359.
Lifang Zhao  1 ,  Huan Yang  2 ,  Yaru Liu  1 ,  Jiayu Tian  1 ,  Lingxuan Gao  1 ,  Linlin Guan  1 ,  Na Cao  1 ,  Ren Li  1 ,  Yuqiong Zhang  1 ,  Dongxing Shi  1 ,  Caihong Wang  3 ,  Jiaji Cheng  1 ,  Shuai Guo  1 ,  Zhihong Zhang  4
Affiliations
  • 1. Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; Yellow River Basin Ecological Public Health Security Center, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China.
  • 2. Taiyuan Center for Disease Control and Prevention, Taiyuan, Shanxi 030000, China.
  • 3. Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi 030032, China.
  • 4. Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; Yellow River Basin Ecological Public Health Security Center, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, Shanxi 030001, China. Electronic address: [email protected].
PMID: 42296917 DOI: 10.1016/j.ecoenv.2026.120359
Abstract

Fine particulate matter (PM2.5) is a major environmental pollutant that poses a significant risk to respiratory health. Ferroptosis represents a key pathogenic mechanism underlying this process. However, the relative contributions of specific PM2.5 components and the potential mechanisms through which they induce pulmonary Ferroptosis remain unclear. This study aimed to compare pulmonary Ferroptosis triggered by PM2.5 components and to elucidate the underlying mechanisms via in vivo and in vitro experiments. The cytotoxicity of PM2.5 exposure on BEAS-2B cells was measured through the CCK-8 assay. The mitochondrial ultrastructural alterations were assessed by transmission electron microscopy (TEM). The levels of ferroptosis-related markers were quantified by qRT-PCR and Western blot. The results indicated that PM2.5 exposure caused mitochondrial damage in mouse lungs, and cellular experiments further revealed water-insoluble components (WICs) as the primary contributors to such damage. Consistently, after exposure to different components of PM2.5, WICs were more potent than water-soluble components (WSCs) in inducing Fe2 +release, ROS production, MDA release, GSH depletion, and alterations in ferroptosis-related markers. Notably, Nrf2 inhibition markedly sensitized cells to PM2.5-induced Ferroptosis, whereas Prdx6 overexpression effectively mitigated this effect. Our results demonstrated that WICs were identified as the primary components responsible for PM2.5-induced Ferroptosis, mediated by disruption of the Nrf2/Prdx6 pathway. These findings offer new insights into the environmental health risks of PM2.5 and establish the Nrf2/Prdx6 axis as a potential therapeutic target for air pollution-related pulmonary diseases.

Keywords
Ferroptosis; Nrf2/Prdx6 pathway; PM(2.5); WICs; WSCs.
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