Co-exposure to polystyrene nanoplastics and cadmium induces apoptosis in intestinal cells: Role of the IP3R/Ca²⁺/STAT3 signaling pathway

The widespread use of plastic products has elevated nanoplastics (NPs) pollution to a critical global concern, with polystyrene nanoplastics (PS-NPs) and cadmium (Cd) emerging as common environmental contaminants whose co-occurrence and combined toxicity increasingly alarm the scientific community. The intestine, as the main xenobiotic exposure site, is a primary target for PS-NPs and Cd exposure-individually or combined. While PS-NPs and Cd’s individual intestinal toxicity mechanisms are well-studied, their combined effects remain poorly understood, especially at the molecular level. This study investigated the combined effects of environmentally relevant concentrations of PS-NPs and Cd on intestinal apoptosis and the regulatory role involving the IP3R/Ca 2+ /STAT3 pathway using both C. elegans and Caco-2 cell models. In C. elegans , 72-hour PS-NPs (10   μg/L) and Cd (5   μg/L) co-exposure induced developmental retardation, intestinal structural abnormalities, and dysregulated expression of apoptosis-related genes along with key components of the IP3R/Ca 2+ /STAT3 pathway. Parallel experiments in Caco-2 cells demonstrated that 24-hour co-treatment with PS-NPs (20   μg/mL) and Cd (0.25   μg/mL) significantly elevated apoptosis rates and triggered endoplasmic reticulum stress. Molecular analyses revealed these effects were mediated through increased IP3R phosphorylation, elevated cytosolic Ca 2+ concentrations, and enhanced phosphorylation of the downstream effector STAT3. Notably, pharmacological inhibition of IP3R (2-APB, 10   μM), Ca²⁺ chelation (BAPTA, 10   μM), or STAT3 phosphorylation (stattic, 5   μM) significantly attenuated PS-NPs and Cd-induced apoptosis. These results establish the IP3R/Ca²⁺/STAT3 axis as a pivotal regulatory switch governing intestinal apoptosis under NP-heavy metal co-exposure, providing mechanistic foundations for environmental risk assessment of combined pollutant exposure.