Cytidine/Uridine monophosphate kinase 2 promotes aflatoxin B1-induced hepatic pyroptosis and inflammation.

Aflatoxin B1 (AFB1), one of the most potent environmental hepatotoxins, exerts its adverse effects through oxidative stress, immune dysregulation, and multiple forms of regulated cell death. However, the upstream molecular mechanisms linking hepatocyte injury to hepatic immune activation remain unclear. In this study, we identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a pivotal regulator of AFB1-induced liver injury. Using AML12 hepatocytes and a chronic AFB1 exposure mouse model, we demonstrated that AFB1 markedly upregulated CMPK2 expression and activated the NLRP3/caspase-1/gasdermin D (GSDMD) pathway, leading to hepatocyte pyroptosis, inflammatory cytokine release, and macrophage infiltration with M1-type polarization. This process further amplified NF-κB signaling, establishing a feed-forward loop of hepatic inflammation. Genetic and pharmacological inhibition of CMPK2 using the selective inhibitor nordihydroguaiaretic acid (NDGA) effectively attenuated hepatocyte pyroptosis, reduced oxidative stress, suppressed macrophage activation, and alleviated hepatic injury in vivo. Collectively, these findings reveal CMPK2 as a central driver of AFB1-induced hepatic inflammation and pyroptosis, and highlight CMPK2 inhibition as a promising strategy for mitigating mycotoxin-associated liver damage.