More than microplastics, nanoplastics may pose a greater toxic effect on humans due to their unique physicochemical properties. Currently, research on lung diseases caused by respiratory exposure to nanoplastics is scarce, with epigenetic mechanisms warranting further investigation. In the present study, we exposed rats to polystyrene nanoplastics (PS-NPs) via an oral-nasal exposure system and found that PS-NPs exposure resulted in emphysema. Mechanistically, PS-NPs entered macrophages and competitively bound to sigma nonopioid intracellular receptor 1 (SIGMAR1), leading to an increase in free zDHHC palmitoyltransferase 14 (zDHHC14). This, in turn, caused elevated palmitoylation of solute carrier family 31 member 1 (SLC31A1) in macrophages, inhibiting its ubiquitination and degradation, thereby enhancing SLC31A1 expression. The increased expression of SLC31A1 promoted cuproptosis of macrophages and elevated tumor necrosis factor-α (TNF-α) secretion, which activated the NLR family pyrin domain containing 3/matrix metallopeptidase 9 (NLRP3/MMP-9) pathway in alveolar epithelial cells (AECs). This process mediated pyroptosis and degradation of extracellular matrix (ECM), resulting in the destruction of alveolar structure and development of emphysema. The findings demonstrate a previously unknown molecular mechanism by which PS-NPs induce emphysema. The findings have implications for the prevention and treatment of respiratory system damage caused by nanoparticles.