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

ABSTRACT

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.