Effects of metal ions on amyloid liquid–liquid phase separation and liquid-to-solid phase transition

Metal ions have emerged as critical factors influencing biomolecular phase separation and are increasingly implicated in the formation, maturation, and pathological transformation of condensates associated with amyloidogenic proteins. Recent studies have shown that metal ions can affect liquid-liquid phase separation and liquid-to-solid phase transition through multiple mechanisms, including electrostatic interactions, direct metal coordination, intermolecular bridging, and metal-induced conformational changes. Depending on the specific proteins and metal ions involved, these interactions can promote, inhibit, or exert only modest effects on phase behavior. In this review, we summarize recent advances in understanding how metal ions alter phase separation in amyloid-forming proteins, with a particular focus on molecular mechanisms underlying these processes. We also discuss the potential impact of metal-dependent phase transitions on protein aggregation pathways and their implications for the development and progression of neurodegenerative diseases.