Cadmium and arsenite rewire redox-linked phosphate metabolism in human iPSC-derived lung organoids

Environmental exposure to redox-active metal and metalloids such as cadmium (Cd) and arsenic (As) during early development poses significant risks to lung health, yet the underlying metabolic mechanisms remain poorly understood. Here, we used human induced pluripotent stem cell (iPSC)-derived lung organoids that recapitulate airway branching morphogenesis to investigate time- and sex-dependent metabolic responses to environmentally relevant Cd and As co-exposure (100 nM). Untargeted high-resolution metabolomics showed pronounced, phase-specific metabolic reprogramming, with early progenitor-like organoids (day 42) exhibiting the greatest sensitivity. Cd and As exposure induced coordinated alterations in redox homeostasis, characterized by expansion of the glutathione pool, perturbation of ubiquinone-related metabolism, and reduced glucose utilization and nucleotide biosynthesis, consistent with increased demand for NADPH. Concomitantly, inositol phosphate metabolism was markedly remodeled, with inositol hexakisphosphate (IP6) emerging as a central metabolic hub linked to nucleotide and pentose phosphate pathway intermediates, suggesting redistribution of phosphate-containing metabolites under redox stress. Sex-dependent differences were observed, with male organoids showing stronger NRF2 activation and inositol phosphate responses, while female organoids exhibited greater depletion of nucleotide intermediates, consistent with differential baseline antioxidant capacity and adaptive metabolic responses. Together, these findings identify a critical developmental window during which Cd and As disrupt metabolic networks of redox balance and phosphate utilization. This study provides a new insight into how redox-active metal mixtures reprogram metabolism during lung development and highlights the importance of developmental stage and biological sex in determining susceptibility to environmental exposures.