¹Taipei City Psychiatric Center, Taipei City Hospital, Songde branch, Department of Psychiatry, Taipei City, Taiwan, ²Taipei Medical University, International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei City, Taiwan, ³Taipei Medical University, International Master/Ph.D. Program in Medicine, College of Medicine, Taipei City, Taiwan, ⁴Taipei Medical University, Graduate Institute of Mind Brain and Consciousness, Taipei City, Taiwan, ⁵Taipei Medical University, Department of Psychiatry, School of Medicine, College of Medicine, Taipei City, Taiwan, ⁶Taipei Medical University, Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei City, Taiwan, ⁷Fu Jen Catholic University, School of Medicine, College of Medicine, New Taipei City, Taiwan

Background: Bipolar disorder (BD) is a severe mental disorder with unclear pathophysiology. Previous studies involving plasma and serum proteomes in BD suggest chronic inflammation is related to the complement system and coagulation cascade. These findings underscore the potential value of platelet studies in understanding BD. Additionally, research indicates that BD patients face an increased cancer risk and that treatment with lithium lowers the cancer risks. There’s also been extensive research on the relationship between platelet and oncogenesis; however, mechanisms associated with oncogenesis in BD patients, and its interplay with platelets, warrant further investigation, particularly the programmed cell death (PD) pathway, which is related to affective disorders and pivotal in regulating the balance between chronic inflammation and carcinogenesis.

Aims & Objectives: This study aims to utilize the platelet proteomic approach in BD patients during manic episodes, to investigate the association between platelet oncoproteins with plasma biomarkers in the PD pathway and pro-inflammatory processes.

Method: Platelet proteomes from 11 BD patients in manic phases (4 males, 7 females) and 11 age- and gender-matched healthy controls (HC) were analyzed using LC-MS/MS. Differentially expressed proteins were identified based on a p-value < 0.05 and a ≥1.2-fold change in relative abundance. The set of differentially expressed proteins was subjected to enrichment analysis using the DAVID Bioinformatics Resource to identify Gene Ontology (GO) terms. These proteins were also mapped onto the Ingenuity Pathway Analysis (IPA) database for pathway analysis. In this process, we mainly focused on oncoproteins. This work focused on the investigation of the relationships between platelet oncoproteins, plasma PD-1/PD-L1 levels, and pro-inflammatory markers, assessed by Pearson correlation analysis.

Results: Pathway analysis indicated the inhibition of pathways related to neoplasia. Among these proteins, two oncoproteins—adapter protein SH3BGRL and tyrosine-protein kinase Yes (YES)—exhibited significant decrease in BD patients compared with HC. Notably, the expression levels of SH3BGRL and YES were both inversely correlated with plasma PD-L1 levels. Additionally, the levels of platelet oncoproteins (YES and SH3BGRL) and plasma markers (PD-1, PD-L1, TNFα, TNFR1, and TNFR2) did not differ significantly between BD patients treated with lithium and those not receiving lithium.

Discussion & Conclusions: This study is the first to combine a platelet proteomic approach with the PD pathway to explore their association focusing on oncogenesis. The SH3BGRL gene has been implicated in tumor suppression through autophagy in humans, although it appears to play an oncogenic role in murine models. YES protein has been linked to increased PD-L1 expression, a key mechanism in immune evasion by tumors. The interaction between SH3BGRL, YES, and PD-L1 may suggest the complex mechanisms underlying the cancer risk in BD. Further investigation is needed to determine whether these findings reflect reactive changes or alternative pathways at play.