Co-exposure to Cadmium and Polystyrene Nanoplastics Intensifies Renal Damage in Mice via the Activation of the PANoptosis Pathway

Cadmium (Cd) and Polystyrene Nanoplastics (PS-NPs) are co-occurring environmental pollutants with potential nephrotoxic effects, yet their combined impact and underlying mechanisms remain unclear. This study aimed to investigate whether co-exposure to Cd and PS-NPs exacerbates renal injury in mice and to determine the role of PANoptosis—a coordinated cell death pathway involving Pyroptosis, Apoptosis, and Necroptosis—in mediating this toxicity. Sixty male Kunming mice were divided into four groups (n = 15): control, Cd (1.5 mg/kg/day), PS-NPs (1 mg/kg/day), and Cd + PS-NPs co-exposure. Treatments were administered via intragastric gavage for 35 days. Body weight, kidney index, histopathology (H&E, Masson, PAS), and ultrastructure (TEM) were evaluated. Molecular activation of PANoptosis was assessed by Western blot, qRT-PCR, immunohistochemistry, and immunofluorescence. Co-exposure significantly reduced body weight and kidney index (p < 0.05) and caused severe glomerular atrophy, tubular necrosis, and collagen deposition. Ultrastructural damage, including mitochondrial vacuolation and nuclear degeneration, was most pronounced in the co-exposure group. Mechanistically, co-exposure synergistically upregulated key markers of Pyroptosis (Caspase-1, Pyrin, GSDMD), Apoptosis (Caspase-8, Bax), and Necroptosis (RIPK1, p-RIPK3, MLKL). Notably, the PANoptosis scaffold protein ASC was markedly increased at both protein and mRNA levels (p < 0.001), indicating PANoptosome activation. Co-exposure to Cd and PS-NPs induces synergistic renal damage in mice, primarily through activation of the PANoptosis pathway. This study reveals a novel mechanism of nano-heavy metal co-toxicity, highlighting PANoptosis as a critical target in environmental nephrotoxicity assessment. Co-exposure to Cd/PS-NPs activates PANoptosis in renal tissue Synergistic renal damage exceeds single Cd or PS-NPs toxicity PANoptosis integrates pyroptosis, apoptosis, and necroptosis pathways