ObjectiveGenetic approaches are increasingly advantageous in characterizing treatment-resistant schizophrenia (TRS). We aimed to identify TRS-associated functional brain proteins, providing a potential pathway for improving psychiatric classification and developing better-tailored therapeutic targets.MethodsTRS-related proteome-wide association studies (PWAS) were conducted on genome-wide association studies (GWAS) from CLOZUK and the Psychiatric Genomics Consortium (PGC), which provided TRS individuals (n= 10,501) and non-TRS individuals (n= 20,325), respectively. The reference datasets for the human brain proteome were obtained from ROS/MAP and Banner, with 8,356 and 11,518 proteins collected, respectively. We then performed colocalization analysis and functional enrichment analysis to further explore the biological functions of the proteins identified by PWAS.ResultsIn PWAS, two statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset, including CPT2 (PPWAS-ROS/MAP= 4.15 × 10−2andPPWAS-Banner= 3.38 × 10−3) and APOL2 (PPWAS-ROS/MAP= 4.49 × 10−3andPPWAS-Banner= 8.26 × 10−3). Colocalization analysis identified three variants that were causally related to protein expression in the human brain, includingCCDC91(PP4 = 0.981),PRDX1(PP4 = 0.894), andWARS2(PP4 = 0.757). We extended PWAS results from gene-based analysis to pathway-based analysis, identifying 14 gene ontology (GO) terms and the only candidate pathway for TRS, metabolic pathways (all P <0.05).ConclusionsOur results identified two protein biomarkers, and cautiously support that the pathological mechanism of TRS is linked to lipid oxidation and inflammation, where mitochondria-related functions may play a role.