Polystyrene nanoplastics exacerbate dibutyl phthalate-induced liver fibrosis through PDGFRα-dependent hepatic stellate cell activation.

Nanoplastic particles (NPs) derived from common polymers such as polyvinyl chloride and polystyrene (PS) act as persistent environmental reservoirs that facilitate the transport and cellular internalization of dibutyl phthalate (DBP), a ubiquitous plasticizer contaminating air, water, soil, and food through plastic leaching. The platelet-derived growth factor receptor α (PDGFRα) pathway is a well-established regulator of hepatic stellate cell (HSC) activation and fibrogenesis; however, its mechanistic involvement in plastic particle-induced hepatotoxicity and its intersection with DBP-mediated fibrosis remain unclear. Using HSC-hepatic cell cocultures (LX-2-HepG2 or LO2) and transcriptomic profiling, we demonstrate that DBP exposure markedly decreases hepatic cellular viability, elevates proinflammatory cytokines (TNF and IL-6), and induces apoptosis. In parallel, DBP stimulates LX-2 proliferation and upregulates fibrogenic markers (TGFB1, COL1A1, ACTA2) along with enhanced secretion of PDGF-A and PDGF-B, thereby reinforcing hepatic cell injury through paracrine signaling. RNA-seq analysis revealed activation of apoptotic and TNF-related pathways in LO2, whereas LX-2 cells exhibited upregulation of oncogenic and PI3K-Akt signaling, collectively promoting a profibrotic transcriptional landscape. In vivo, both PDGFRα antibody neutralization and pharmacological inhibition with imatinib significantly attenuated DBP-induced hepatic fibrosis and inflammatory gene expression, confirming PDGFRα's central role in DBP toxicity. Polystyrene nanoplastics (PS-NPs) were rapidly internalized by PDGFRα-positive primary HSCs within 24 h, leading to increased PDGFRα and PI3K expression. Co-exposure to PS-NPs and DBP resulted in synergistic hepatotoxicity and exacerbated fibrotic injury, demonstrating compounding effects of mixed environmental pollutants. Collectively, these findings identify PDGFRα as a mechanistic nexus linking DBP and PS-NPs exposure to hepatic fibrosis and highlight its potential as a therapeutic target for environmentally induced liver disease. The results further underscore the importance of co-exposure paradigms in evaluating the health risks of complex contaminant mixtures.