Protein corona proteomics characterizes low-abundance plasma protein signatures and highlights ferroptosis-associated signals in uremic hemodialysis patients.

Patients with uremia undergoing long-term hemodialysis are prone to multi-organ complications, but the underlying molecular mechanisms remain unclear. Ferroptosis, an iron-dependent form of cell death, has been linked to inflammation and organ damage. Its role in hemodialysis-related pathology, however, has not been well characterized. In this study, we systematically profiled low-abundance plasma proteins from six hemodialysis patients and eight healthy controls using a protein corona-based enrichment technique to enhance detection sensitivity. A total of 183 differentially expressed proteins (DEPs) were defined based on a fold-change threshold (≤ 0.25 or ≥ 4), including 101 upregulated and 82 downregulated proteins. Notably, pathway enrichment analysis highlighted the ferroptosis pathway, with altered abundance of proteins including TFRC, ALOX15, PRNP, CYBB, and ACSL1, suggesting a potential association of ferroptosis-related signals with hemodialysis-related complications. To complement the proteomic analysis, enzyme-linked immunosorbent assay (ELISA) was performed in an independent cohort. ALOX15 showed a significant and reproducible increase in plasma levels (P < 0.0001), consistent with the proteomic results. Other ferroptosis-related candidates warrant further evaluation and independent validation in larger cohorts. Furthermore, drug target prediction based on DEP data identified N-oleoyldopamine, luteolin, and catechol as potential compounds targeting the five ferroptosis-related molecules. Collectively, this study provides an exploratory plasma proteomic resource and suggests that ferroptosis-associated plasma protein changes may be relevant to hemodialysis-related complications, warranting further validation. Collectively, this study provides an exploratory plasma proteomic resource and offers initial insights into ferroptosis-associated plasma protein changes in hemodialysis patients.