Pyroptosis mediated by Parkin-NLRP3 negative feedback loop contributed to Parkinson’s disease induced by rotenone

•A Parkin-NLRP3 negative feedback loop participated in rotenone induced PD.•Rotenone caused pyroptosis via NLRP3 inflammasome in dopamine neurons.•Rotenone caused Parkin inactivity and failed to ubiquitinated NLRP3.•MCC950 restored Parkin activity and inhibited NLRP3-mediated pyroptosis. Rotenone remains an efficient pesticide used extensively in agriculture, leading to neurotoxicity and the increase of the prevalence of Parkinson’s disease (PD). Previous studies indicated that Parkin, a neurohomeostasis regulatory factor, and NOD-like receptor protein 3 (NLRP3), a core factor driving the inflammatory response, interacted with each other, which affected neuroinflammation occurrence. However, whether rotenone accelerated PD progression via Parkin-NLRP3 loop and the specific mechanisms were still unclear. Here, a novel negative feedback mechanism of Parkin-NLRP3 that regulated PD caused by rotenone was certified. Rotenone treatment induced neurodegeneration in vitro- and vivo-models. The activation of NLRP3 inflammasome and Parkin was increased and decreased, respectively, and the expression of pyroptosis related proteins was up-regulated, because of the addition of rotenone. Notably, the overexpression of Parkin promoted NLRP3 ubiquitination, which down regulated pyroptosis mediated by NLRP3, protected mitochondrial function as well as preventing neurodegeneration. Additionally, the NLRP3 inhibitor MCC950 restored the activation of Parkin and down regulated pyroptosis mediated by NLRP3 in rotenone-induced PD. It was revealed that the Parkin-NLRP3 negative feedback loop participated in rotenone-induced PD by regulating pyroptosis, representing a new idea for the prevention and treatment of neurodegenerative diseases.