Arachidonic acid metabolite prostaglandin E2 attenuates diethylhexyl phthalate-induced hepatotoxicity through promoting macrophage M2 polarization

  • Food Chem Toxicol. 2025 Aug:202:115501. doi: 10.1016/j.fct.2025.115501.
Miao Xu  1 ,  Lijuan You  2 ,  Yaru Tian  3 ,  Jiuming Yan  1 ,  Lei Shi  1 ,  Yi Wan  3 ,  Xudong Jia  4 ,  Hui Yang  5 ,  Wen Hu  6
Affiliations
  • 1. Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, China; School of Public Health, Shandong Second Medical University, Weifang, 261053, China.
  • 3. Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, 100021, China.
  • 4. NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, China.
  • 5. NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, China; School of Public Health, Shandong Second Medical University, Weifang, 261053, China. Electronic address: [email protected].
  • 6. Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 40318824 DOI: 10.1016/j.fct.2025.115501
Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD), exacerbated by endocrine disruptors like phthalate-plasticizers, underscores the need to understand their impact on hepatic lipid metabolism. Although the suppression of hepatic macrophage M2 polarization is known to contribute to diethylhexyl phthalate (DEHP)-induced hepatic lipid accumulation, the role of intracellular metabolism in macrophages remains unclear. Here, we investigated the role of arachidonic acid metabolism-a key regulator of M2 macrophage polarization-and its metabolite prostaglandin E2 (PGE2) in DEHP-induced hepatic lipid disorders. DEHP exposure disrupted lipid metabolism and reduced hepatic macrophages. Genomic and metabolomic analyses of mice revealed a strong correlation between decreased hepatic M2 macrophages and perturbed arachidonic acid metabolism. Elevating the PGE2 level attenuated the inhibition of M2 macrophages caused by DEHP or its metabolite mono- (2-ethylhexyl) phthalate (MEHP) both in vitro and in vivo. Additionally, PGE2-induced M2 macrophages alleviated DEHP/MEHP-induced lipid metabolism disorders. In summary, arachidonic acid metabolism and PGE2 are critical metabolic regulators in DEHP-induced lipid metabolism disorders. This study identifies a novel metabolic target related to macrophage polarization in phthalates toxicity and provides a foundation for therapeutic strategies against endocrine disruptor-associated NAFLD.

Keywords
Arachidonic acid metabolism; Diethylhexyl phthalate; Lipid metabolism disorders; Macrophages; Prostaglandin E2.
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