Polychlorinated biphenyls (PCBs) are one of the most refractory organic environmental pollutants that ubiquitous existence in nature. Due to the polymorphism of their metabolic pathway and corresponding downstream metabolites, PCBs’ toxicities are complicated and need extended investigation. In the present study, we discovered a novel regulatory mechanism of PCB quinone metabolite-driven programmed cell death (PCD), namely, necroptosis. We first confirmed that PCB quinone induces cancerous Hela and MDA-MB-231 cells necroptosis via the phosphorylation of mixed lineage kinase domain-like MLKL (p-MLKL). Then, we found that PCB quinone-stimulated p-MLKL enhances exosome biogenesis and secretion. Exosome interacts with p-MLKL and releases p-MLKL to the outside of the cell, and ultimately alleviating PCB quinone-induced necroptosis. The inhibition of exosome secretion by GW4869 significantly elevated necroptotic level, indicating the establishment of a short negative feedback loop of MLKL-exosome secretion upon PCB quinone challenge. Since exosome-mediated signaling showed great implications in various human diseases, this work may provide a new mechanism for PCBs-associated toxicity.

多氯联苯（PCB）是自然界中普遍存在的最难降解的有机环境污染物之一。由于多氯联苯的代谢途径和相应的下游代谢产物具有多态性，因此其毒性很复杂，需要进一步研究。在本研究中，我们发现了PCB醌代谢产物驱动的程序性细胞死亡（PCD）的新调节机制，即坏死病。我们首先证实PCB醌可通过以下途径诱导癌性Hela和MDA-MB-231细胞坏死混合谱系激酶域样MLKL（p-MLKL）的磷酸化。然后，我们发现PCB醌刺激的p-MLKL增强了外泌体的生物发生和分泌。外泌体与p-MLKL相互作用并将p-MLKL释放到细胞外部，并最终缓解PCB醌诱导的坏死病。GW4869对外泌体分泌的抑制作用显着提高了坏死性肾病的水平，这表明在PCB醌激发后，MLKL外泌体分泌的负反馈回路短。由于外泌体介导的信号转导在各种人类疾病中具有重大意义，这项工作可能为多氯联苯相关毒性提供新的机制。