2. Academic Validation
  3. Dibutyl phthalate exposure-induced AhR activation drives ferroptosis and HMGB1/TLR4-mediated inflammatory liver injury via NRF2-HO-1 signaling

Dibutyl phthalate exposure-induced AhR activation drives ferroptosis and HMGB1/TLR4-mediated inflammatory liver injury via NRF2-HO-1 signaling

  • Environ Pollut. 2026 Jun 1:398:128010. doi: 10.1016/j.envpol.2026.128010.
Zixu Li 1,  Muge Xu 1,  Yahan Zhang 1,  Yao Chen 1,  Weiwei Feng 1,  Ting Zhao 2,  Liuqing Yang 2,  Guanghua Mao 3,  Xiangyang Wu 4
Affiliations

Affiliations

  • 1 School of the Environment and Safety Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China.
  • 2 School of Chemistry and Chemical Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China.
  • 3 School of the Environment and Safety Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China; School of the Environment and Safety Engineering, Key Laboratory of Zhenjiang, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China. Electronic address: [email protected].
  • 4 School of the Environment and Safety Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China; School of the Environment and Safety Engineering, Key Laboratory of Zhenjiang, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China. Electronic address: [email protected].
PMID: 41887355 DOI: 10.1016/j.envpol.2026.128010
Abstract

The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the Aryl Hydrocarbon Receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or Ferroptosis significantly attenuated these changes, highlighting the potential of AhR and Ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR-NRF2/HO-1-ferroptosis-HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.

Keywords

Aryl hydrocarbon receptor; Dibutyl phthalate; Ferroptosis; HMGB1; Hepatotoxicity.

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