Exposomic analysis of emerging contaminants associated with lung cancer risk and recurrence using pseudo-targeted LC-MS/MS.

Lung cancer remains the leading cause of cancer-related mortality. The rising incidence among never-smokers underscores the role of environmental exposures, particularly contaminants of emerging concern (CECs) -a diverse group of largely unregulated chemicals with potential carcinogenicity. Yet, their links to lung cancer risk and prognosis are not well defined. To address this, we developed a robust and sensitive pseudo-targeted LC-MS/MS exposomics platform using 97 reference standards to semi-quantitatively profile 350 serum CECs in a hospital-based cohort comprising 570 lung cancer patients and 307 healthy controls. The method demonstrated high analytical reliability detecting 228 CECs across all participants. Several compounds-including monomethyl phthalate (MMPA), perfluorooctanesulfonic acid, and simazine-were significantly elevated in patients. Mixture models confirmed synergistic effects of co-exposures, and among 75 postoperative recurrence cases, MMPA, bisphenol G, and Irganox 245 emerged as. Key recurrence-associated chemicals. Absolute quantification revealed significantly higher serum MMPA levels in patients (83.09 μg/L) compared to controls (57.19 μg/L). Proteomic profiling of MMPA-exposed A549 lung cancer cells showed dysregulation in pathway related to chromatin remodeling, autophagy, cytochrome P450 metabolism, and immune function. This study integrates exposomics and proteomics to identify CECs linked to lung cancer development and recurrence, offering novel insights into environmental contributions and potential molecular targets in disease progression.