Polystyrene Nanoplastics Drive β‐Cell Dedifferentiation Through Dendritic Cell‐Intrinsic MHC‐I‐Dependent Inflammatory Crosstalk

Environmental nanoplastic exposure is linked to metabolic disorders, yet its impact on pancreatic immune-endocrine homeostasis and β-cell identity regulation remains poorly defined. Rats were exposed to polystyrene nanoplastics(PS-NPs) for 12 weeks under a control or high-fat diet. Pancreatic injury and phenotypes were assessed biochemically, histologically, and ultrastructurally; single-nucleus RNA-seq delineated cell-specific transcription and intercellular networks. Mechanistic validation used cell co-cultures with MHC-I modulation, and translational relevance was assessed in a human exposure cohort. Chronic PS-NPs exposure exacerbated hyperglycemia and glucose intolerance, and induced pancreatic damage. Single-nucleus transcriptomics identified β cells and dendritic cells (DCs) as the most responsive populations. PS-NPs drove β-cell dedifferentiation, characterized by downregulation of key identity markers (Mafa, Pdx1, Nkx6.1). Concurrently, DCs exhibited a maturation-like phenotype with robust upregulation of MHC-I and inflammatory pathways. Ligand-receptor analysis revealed enhanced proinflammatory crosstalk between DCs and β cells. Functionally, MHC-I upregulation in DCs activated TLR4/NF-κB signaling and drove β-cell dedifferentiation in vitro. Consistently, occupationally exposed individuals showed elevated circulating HLA-A levels and metabolic abnormalities. These findings identify an MHC-I-dependent DCs-β-cell inflammatory axis through which PS-NPs disrupt pancreatic immune-endocrine homeostasis and promote β-cell dedifferentiation, revealing mechanisms underlying PS-NPs-induced metabolic dysfunction.