Lipid disturbance and neuroinflammation contribute to Aflatoxin B1-linked Parkinsonism: an in vitro, in vivo, and Parkinsonism patients' integrating evidence.

Aflatoxin B1 (AFB1) is a ubiquitous food contaminant with established hepatorenal toxicity, but its contribution to Parkinsonism remains unclear. We investigated whether AFB1 exposure promotes Parkinsonism pathology through lipid disturbance and lysophosphatidylserine (Lyso-PS)-driven neuroinflammation. Quantification of serum AFB1-albumin adducts and targeted lipidomic analysis were conducted on serum samples from 12 patients with Parkinsonism and 12 controls subjects. Parallel experiments in C57BL/6J mice exposed to AFB1 (1.5 mg/L in drinking water for 6 weeks) included motor behavioral testing, midbrain histopathology, untargeted lipidomics, and cytokine profiling. Mechanism validation was conducted in MN9D dopaminergic neurons by modulating Lyso-PS metabolism and signaling. Patients with Parkinsonism exhibited elevated serum AFB1-albumin levels. Meanwhile, Lyso-PS was identified as the only subclass that increased significantly in human serum lipidomic analysis compared to the control group. Chronic AFB1 exposure in mice induced motor deficits, dopaminergic neuron loss, α-synuclein accumulation, and robust systemic and midbrain inflammation, accompanied by midbrain Lyso-PS enrichment and upregulation of Abhd16a and Gpr34. In MN9D cells, AFB1 increased Lyso-PS, P65 mRNA levels, α-synuclein, and pro-inflammatory cytokines, whereas Abhd16a knockdown or inhibition and Gpr34 blockade attenuated these effects. In line with observation in serum samples from patients with Parkinsonism, Lyso-PS (15:0) and Lyso-PS (16:0) levels were increased in the midbrain of mice after AFB1 exposure. Collectively, these findings suggest that AFB1 disrupts Lyso-PS metabolism and induces neuroinflammation in the midbrain, potentially through the Lyso-PS/Gpr34/NF-κB axis, thereby contributing to Parkinsonism-like motor deficits. Lyso-PS (15:0) and Lyso-PS (16:0) emerge as promising metabolic biomarkers of the risk of AFB1-associated neurotoxicity. Further validation in larger clinical cohorts and additional in vivo causal studies are warranted.