Abstract

AFB 1 exposure induces Parkinsonism-like motor deficits and midbrain dopaminergic injury in C57BL/6J mice. • AFB 1 exposure alters the midbrain lipid profile and elevates pro-inflammatory Lyso-PS species. • The Lyso-PS/Gpr34/NF-κB axis contributes to AFB 1 -induced neuroinflammation and PD-like neuropathology in C57BL/6J mice. • AFB 1 -linked elevation of Lyso-PS (15:0) and Lyso-PS (16:0) are observed in the serum of PD patients and in the midbrains of mice. Aflatoxin B 1 (AFB 1 ) is a ubiquitous food contaminant with established hepatorenal toxicity, but its contribution to Parkinsonism remains unclear. We investigated whether AFB 1 exposure promotes Parkinsonism pathology through lipid disturbance and lysophosphatidylserine (Lyso-PS)-driven neuroinflammation. Quantification of serum AFB 1 -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 AFB 1 (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 AFB 1 -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 AFB 1 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, AFB 1 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