Schizophrenia is a severe psychiatric disorder with a lifetime prevalence of approximately 1 %, characterized by high rates of mortality and disability (Jauhar et al., 2022). A European study reported that the unemployment rate among individuals with schizophrenia ranged from 70 % to 90 % (Marwaha et al., 2007). Schizophrenia is considered a complex polygenic disorder resulting from the interplay of genetic and environmental factors. Despite its substantial social burden, the underlying pathogenic mechanisms remain unclear. Lipids play a crucial role in the nervous system, regulating vesicle fusion, ion flux, and cellular communication, as well as influencing protein trafficking, cell recognition, and signaling. Lipids make up half of the brain's dry weight, with phospholipids forming the structural backbone of neural membranes (Piomelli et al., 2007). Fatty acids (FAs), as essential components of phospholipids, are integral to cellular function. Dysregulated phospholipid and FA metabolism have been implicated in the pathophysiology of schizophrenia (Fenton et al., 2000; Horrobin, 1998; Horrobin et al., 1994).

Circulating FA levels are determined not only by dietary intake but also by endogenous biosynthesis and metabolic regulation. Metabolomic studies of both brain and peripheral tissues have revealed abnormalities in FA profiles among individuals with schizophrenia. Reduced levels of polyunsaturated fatty acids (PUFAs) have been reported in the postmortem brains of schizophrenia patients. Notably, significant decreases have been observed in docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) within the orbitofrontal cortex (McNamara et al., 2007), docosapentaenoic acid (DPA, 22:5n-6) within the hippocampus (Hamazaki et al., 2010), and docosatetraenoic acid (DTA, 22:4n-6) within the amygdala (Hamazaki et al., 2012), among others. Dietary interventions targeting FA intake have emerged as a promising approach for preventing the onset and progression of brain disorders (Haast and Kiliaan, 2015). Aberrant FA metabolism in schizophrenia may contribute to disease pathophysiology by affecting neuronal function (Zhao et al., 2023b), white matter integrity (Tabata et al., 2024; Zhao et al., 2023a), and neuroinflammatory or oxidative stress pathways (González-Castro et al., 2024; Yeo et al., 2023).

Similar findings have been reported in studies examining FA levels in red blood cell membranes of schizophrenia patients. For instance, compared to healthy controls, individuals with first-episode psychosis (FEP) exhibited reductions of 18 %, 26 %, and 36 % in AA, DHA, and DPA concentrations, respectively (Reddy et al., 2004). Case-control studies based on serum or plasma metabolomics have also revealed abnormalities in FA metabolism in schizophrenia. Elevated levels of glycerate and eicosenoic acid suggested increased FA catabolism in individuals with schizophrenia (Yang et al., 2013). A targeted metabolomics study further identified higher levels of monounsaturated fatty acids (MUFAs) and n-6 PUFAs (Yang et al., 2017).

FA levels in individuals with schizophrenia are influenced by antipsychotic medication use (Arvindakshan et al., 2003; Khan et al., 2002). For example, plasma linoleic acid (LA, C18:2n-6) and gamma-LA (C18:3n-6) levels in schizophrenia patients decreased after the use of risperidone or olanzapine (Song et al., 2023). Alterations in FA profiles in schizophrenia patients have been reported to be closely associated with oxidative stress and inflammatory responses (Janssen and Kiliaan, 2014; Martinat et al., 2021). Additionally, dysregulated expression of genes involved in FA metabolism may play a critical role in the onset and progression of the disorder (Hamazaki et al., 2016; Liu et al., 2009; Tang et al., 2012). Overall, abnormal FA metabolism in schizophrenia appears to be complex, potentially involving multiple pathways and intricate interactions among various biochemical markers.

Prospective study designs are crucial for understanding the impact of FAs on schizophrenia risk, as they help overcome the limitations of reverse causation often observed in case-control studies. The large prospective cohort of the UK Biobank offers a valuable platform for this research, incorporating not only plasma FA data but also blood biochemical biomarkers. This study aimed to investigate the relationship between plasma FAs and the risk of developing schizophrenia using data from the UK Biobank. Specifically, the study has two main objectives: first, to evaluate the associations between plasma FAs and the risk of schizophrenia; second, to explore the potential mediating role of blood biomarkers in these associations.