Ameliorative effects of Urolithin A against Cadmium-induced NLRP3-mediated pyroptosis and cognitive deficits via regulating Aryl hydrocarbon receptor signaling

Cadmium (Cd) is an important environmental and industrial pollutant that induces neurotoxicity and neurobehavioral disorders in animals. Urolithin A (UA), a gut microbial-derived metabolite from polyphenolic compounds, exhibits potent neuroprotective effects in neurological disorders. Herein, we evaluated the ameliorative impact of UA on Cd exposure-evoked hippocampal injury and cognitive deficits in mice and disclosed the underlying molecular mechanisms. The results demonstrated that UA administration markedly mitigated hippocampal neuronal/synaptic injury and cognitive impairments in Cd-exposed mice. Mechanically, UA administration suppressed Cd exposure-triggered activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and subsequent neuronal pyroptosis in mice hippocampi and SH-SY5Y cells. Moreover, UA administration inhibited Cd-induced AhR activation and reduced the expression of CYP1A1, leading to mtROS elimination in vivo and in vitro . In conclusion, our findings revealed that UA mitigated Cd stress-driven aberrant NLRP3 inflammasome activation and its-mediated neuronal pyroptosis by promoting mtROS clearance, partly via the inhibition of the AhR-CYP1A1 signaling pathway, which ultimately contributed to the attenuation of neuronal/synaptic damage and cognitive deficits.