Gum Arabic Modulates Redox–Ionic Microenvironments via Rheology and Kinetics to Induce Selective Cytotoxicity in Colorectal Cancer Cells

Background: Gum Arabic (GA) is a natural polysaccharide widely recognized for its antioxidant and anti-inflammatory properties; however, its functional behavior as a biopolymeric gel and the mechanisms underlying its selective effects on cancer-related redox microenvironments remain insufficiently characterized. It is imperative to note that the interaction between its physicochemical properties and its biological activity in colorectal cancer remains to be fully clarified. Methods: This study aimed to evaluate the antineoplastic potential of GA in human colorectal cancer (CRC) cell lines (HT-29 and HCT-116) compared to normal fibroblasts (MRC-5) using the MTS assay. Oxidative stress-related molecular responses were assessed by quantitative PCR analysis of GPX4, GSTA2, CAT, NFKB, and SOD1 expression. In parallel, extracellular concentrations of key metal ions (Fe²⁺, Zn²⁺, Mn²⁺, Mg²⁺, Cu²⁺, and Al³⁺) were quantified following GA exposure. To establish its functional gel characteristics, rheological measurements were performed to assess viscosity and shear-dependent behavior, and USP-compliant in vitro kinetic studies were conducted to evaluate time-dependent release properties. Results: GA induced dose-dependent cytotoxicity in HT-29 and HCT-116 colorectal cancer cells, while MRC-5 fibroblasts exhibited comparatively higher viability across the tested concentration range, indicating reduced sensitivity in normal cells. Rheological analysis revealed concentration- and ion-dependent viscoelastic behavior, identifying a 10% (<i>w</i>/<i>w</i>) GA formulation as optimal due to its balanced low-shear viscosity and controlled shear-thinning properties. Kinetic studies demonstrated a defined, diffusion-governed release profile under physiologically relevant conditions. At the molecular level, significant upregulation of GPX4 and GSTA2 was observed in both cancer cell lines, whereas NFKB expression increased selectively in HT-29 cells, with no notable changes in CAT or SOD1 expression. Additionally, GA treatment resulted in marked increases in Fe²⁺, Zn²⁺, and Mn²⁺ levels, indicating modulation of the redox–ionic microenvironment. Conclusions: These findings demonstrate that GA functions as a natural, ion-responsive biopolymeric system with defined rheological and kinetic properties, capable of selectively targeting colorectal cancer cells through coordinated genetic and ionic regulation of oxidative stress. Collectively, the results position GA as a promising functional gel-based platform for future redox-modulated therapeutic strategies in colorectal cancer.