Methcathinone disrupts glycerophospholipid metabolism and selectively activates the p38/COX-2 Axis to induce anxiety-like behaviour in zebrafish.

receptor subunits, and the CB1 receptor, alongside the upregulation of stress-responsive genes (mapk14b and ptgs2a). Pharmacological rescue with the p38 inhibitor SB203580 reversed the anxiety-like behavioural deficits and the associated downstream molecular changes, confirming the causal role of the p38/COX-2 pathway. Thus, methcathinone induces anxiety-like behaviour through a coordinated "lipid-signalling-neurotransmitter" axis. While strongly correlated with upstream glycerophospholipid depletion, the anxiety phenotype is directly driven by selective p38/COX-2 activation, causing impaired GABAergic and cannabinoid inhibitory neurotransmission. This study provides a foundational mechanistic framework for methcathinone-induced neurotoxicity and highlights potential molecular biomarkers for future evaluations of the ecological risks associated with synthetic cathinone contamination in aquatic systems.