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

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.