Small Molecules as Modulators to Prevent Mucin Aggregation via Delaying Liquid-to-Solid Phase Transition

Aberrant mucin aggregation plays a central role in the pathogenesis of multiple mucosal disorders, yet the molecular determinants governing this process under cellular conditions remain poorly understood. Mucins are heavily glycosylated polyanionic proteins whose solubility is disrupted by elevated calcium concentrations, acidic pH, and macromolecular crowding conditions, leading to pathological aggregation. Here, we systematically investigate mucin aggregation under physiologically relevant stressors and evaluate the inhibitory potential of three structurally distinct bioactive compounds: Scopolamine (SCP), Quercetin (QUE), and Epigallocatechin-3-gallate (EPGG). All three bioactives suppress mucin aggregation in a concentration and time-dependent manner, with SCP showing better efficacy through electrostatic competition under acidic conditions, while QUE and EPGG act via hydrogen bonding and hydrophobic interactions. Although bioactives do not alter mucin condensate morphology, they significantly reduce internal molecular dynamics. Permeability profiling further identifies SCP as a promising systemically accessible modulator. Collectively, these findings provide mechanistic insight into mucin aggregation and highlight small-molecule bioactives as potential therapeutic modulators of mucin-associated pathologies.