Immune dysregulation, particularly inflammation, may contribute significantly to the pathophysiology of schizophrenia (SZ). Autophagy is an essential cellular process that maintains neuroimmune homeostasis, but its relationship with inflammation in SZ remains unclear. Eicosapentaenoic acid (EPA), an omega (n)-3 polyunsaturated fatty acid (PUFA), was reported to exert therapeutic effects by modulating inflammation. Here, we hypothesized that EPA alleviates SZ-related behavioral and neurochemical abnormalities via autophagy regulation. Transcriptomic analysis of peripheral blood from SZ patients revealed reduced autophagic markers (BECLIN1, LC3B), which were negatively correlated with symptom severity, while P62 levels were increased, which was positively correlated with symptoms severity. SZ patients also showed an altered n-3 PUFA profile (reduced EPA and DHA, while elevated n-6/n-3 ratio). In a mouse model of SZ induced by maternal immune activation, lower Beclin1, an autophagic marker, was observed in the brains of mice. EPA treatment ameliorated SZ-like behaviors, upregulated Beclin1 expression, rebalanced glial activation toward anti-inflammatory and neuroprotective states. EPA also suppressed pro-inflammatory cytokines (IL-6, TNF-α), increased IL-10 and decreased DA/5-HT ratio in the prefrontal cortex and restored the n-6/n-3 PUFA ratio. Notably, EPA effects were largely blocked by co-administration of an autophagy inhibitor 3-methyladenine (3-MA), whereas these effects were recovered following treatment with the autophagic activator rapamycin. EPA supplementation also increased brain DHA levels, suggesting that downstream DHA-related mechanisms may additionally contribute to the observed effects. Together, these findings indicate that autophagic impairment is associated with neuroimmune and neurochemical abnormalities in SZ and support the autophagic function involved in EPA therapeutic effects on SZ-like changes.
