Reprogramming of fatty acid metabolism induced by environmental pollutant exposure and its role in the toxic effects of environmental pollutants.

Fatty acids (FAs) are vital biomolecules that serve not only as energy substrates but also as bioactive molecules, moieties of other lipids such as phospholipids and triglycerides, structural components of membranes, and precursors to other bioactive molecules. Environmental pollutants, are ubiquitous across environmental, wildlife, and human systems and disrupt FA homeostasis by targeting FA receptors and their associated metabolic networks. Although pollutant-induced disruption of FA metabolism is increasingly recognized, existing studies and reviews have often focused on individual pollutant classes, single receptors, or isolated metabolic processes, which has limited an integrated understanding of how chemically diverse pollutants converge on shared FA metabolic programs. This review provides a cross-pollutant synthesis of mechanistic insights into pollutant-induced disturbances in FA metabolism, focusing on receptor-mediated FA synthesis, oxidation, transport, storage, and utilization for the synthesis of other lipids. We review how pollutants interact with FA receptors and modulate downstream metabolic pathways, thereby altering the levels of FAs and other metabolites and contributing to toxic effects in multiple tissues. This review discusses several receptor-mediated signaling cascades and downstream metabolic pathways that drive pollutant-induced FA metabolic reprogramming and subsequent lipid accumulation. By delineating the pollutant-receptor-metabolite axis, this review provides a unifying framework for understanding how environmental pollutants across major classes drive metabolic reprogramming and for identifying potential intervention targets to mitigate their associated toxicity.