Estradiol Reshapes Cell-Type-Dependent Basal Redox Set-Points in Colorectal Carcinoma Cells

Background/Objectives: Since redox balance is critical to colorectal cancer cell survival, and estradiol, a potent antioxidant, correlates with reduced disease incidence, understanding the redox basis of cellular responsiveness to estradiol is essential for advancing therapeutic insight. This study evaluates the adaptive and maladaptive redox responses of colorectal carcinoma cells to estradiol treatment by defining the basal redox set-point as the intracellular balance between pro-oxidants and antioxidants. Methods: Human colorectal cancer cell lines HCT-116 and SW-480 were treated for 24 h with pregnancy-range and pharmacological-range concentrations of estradiol. Redox biomarkers (superoxide anion/O₂^.-, hydrogen peroxide/H₂O₂, nitric oxide/NO, reduced glutathione/GSH and oxidized glutathione/GSSG), cell viability, and basal migration were analyzed. Correlation, network topology, PCA, and Jaccard similarity analyses were applied to characterize basal redox set-points and quantify estradiol-induced changes in redox profiles in the two cell lines. Results: HCT-116 cells exhibited an O₂^.--centered redox set-point associated with NO and GSH. SW-480 cells displayed a H₂O₂-centered redox set-point associated with NO and GSH. In HCT-116 cells, estradiol triggered a maladaptive response associated with antioxidant activation and reduced proliferation. Conversely, SW-480 cells exhibited an adaptive response characterized by modulation of NO levels and the GSH pool and associated with increased proliferation. Conclusions: These findings identify redox set-point organization as a potential determinant of estradiol responsiveness in colorectal cancer cells. From a clinical perspective, characterizing basal redox set-points in patient-derived tumor cells may enable stratification of colorectal cancer patients by predicted responsiveness to redox-modulating therapies, informing personalized treatment.