<p>Dermal exposure to polycyclic aromatic hydrocarbons (PAHs) and UV irradiation in occupational and environmental settings poses a health risk by inducing skin toxicity, including immunomodulatory effects. This study investigated the effects of benzo[a]pyrene (B[a]P), a well-characterized PAH, at three concentrations (0.04 nM, 4 nM, and 4 µM) and UV irradiation on human monocytic U937 cells, employing both single and combined exposure scenarios. An integrated metabolomics and toxicological approach was utilized to assess cellular responses, with a focus on understanding the immunometabolic effects of these exposures. Our findings revealed that only the highest B[a]P concentration in combination with UV irradiation resulted in significant metabolic dysregulation and impaired cellular function. Notably, we observed a pronounced downregulation of glutaminolysis, a critical metabolic pathway for cellular energy production and biosynthesis. This was evidenced by decreased levels of glutamate and key intermediates within the tricarboxylic acid cycle (e.g., succinate, fumarate, malate, and citrate), as well as reduced levels of glycine, a precursor for glutathione synthesis. In parallel, toxicological assays revealed increased levels of oxidative stress markers, lipid peroxidation, and enhanced DNA damage. Furthermore, the combined exposure led to alterations in tryptophan metabolism and dysregulation of lipid species, particularly sphingolipids and phosphatidylinositols. These findings lead us to propose the hypothesis that metabolic disruption, specifically the impairment of glutaminolysis, initiated a cascade of events, including increased oxidative stress, lipid peroxidation, and ultimately, ferroptosis in our study. Our results indicate that the combined exposure to UV irradiation and B[a]P can induce immunometabolic reprogramming and significantly contribute to the pathogenesis of inflammatory skin diseases.</p>