Polystyrene-microplastics and Emamectin Benzoate co-exposure induced lipid remodeling by suppressing PPARα signals to drive ACSL4-dependent ferroptosis and carp splenic injury

Microplastics (MPs) and Emamectin Benzoate (EMB) were identified as hazardous environmental pollutants, frequently coexisting in aquatic ecosystems, posing potential risk in the immune system of human and animal. However, the hazards of concurrent exposed to MPs and EMB on the carp spleen, and the specific mechanisms remain unclear. Here, we employed MPs and EMB-exposed carp models, and cultured splenocytes in vitro, to demonstrate that PPARα signals suppression underlay MPs and EMB-induced carp spleen injury, based on transcriptomics and lipomics analysis. This suppression exacerbated the buildup of polyunsaturated fatty acid (PUFA), and promoted ACSL4 expression, resulting in increased lipid peroxidation. Further studies found that the accumulation of lipid peroxides predominantly occurred in the mitochondria, which evoked mitochondrial homeostasis imbalance and compromised mitochondrial function, thereby initiating ferroptosis. Additionally, enhancing PPARα signaling, inhibiting ACSL4, or scavenging mitochondrial ROS was favor of mitigating accumulation of lipid peroxides, reducing mitochondrial damage and inhibiting ferroptosis. Notably, MPs and EMB co-exposure caused more severe damage than single exposure. These findings uncovered a potential mechanism, involving PPARα signaling inhibition by MPs and EMB co-exposure, which evoked lipid remodeling and increased ACSL4, to drive ferroptosis and carp splenic injury. This study highlighted the potential hazards to the aquaculture environments where co-exposure of MPs and EMB and provided reference for environmental toxicology research and the sustainable development of the aquaculture industry.