Zinc Complexation Overcomes the Context-Dependent Metabolic Effects of Curcumin in TNBC: Molecular Insights from TLR4/MD-2 Targeting

A critical yet frequently overlooked factor is the tumor’s metabolic profile. Diabetes and chronic moderate hyperglycemia are known risk factors for triple-negative breast cancer (TNBC) that do not respond to hormonal therapy. So, identifying novel therapeutic targets and developing more effective treatments is needed. One of the key pathways involved in the aggressive nature of TNBC is the Toll-like receptor 4 (TLR4) signaling cascade. To this end, curcumin (CUR) has shown effects consistent with modulating inflammatory stress by inhibiting TLR4/MD-2. This study evaluated CUR at concentrations observed in the bloodstream (0.025–25 ng/mL) in MDA-MB-231 TNBC cells under different glucose conditions (normal, moderate, and severe hyperglycemia) and inflammatory states (LPS-induced), using cell viability assays and molecular docking. A zinc complex (Zn–CUR) was also used. Results were validated through cell viability assays. Under severe hyperglycemia, CUR unexpectedly increased cell viability in a dose-dependent manner, while Zn–CUR had no activity across all glucose levels. In LPS-induced inflammation, CUR exhibited a biphasic, dose-dependent response, being protective at mid-level doses but cytotoxic at higher doses, whereas Zn–CUR showed more consistent effects, consistent with modulation of inflammatory stress. Molecular docking suggests that Zn–CUR binds more stably within the MD-2 hydrophobic pocket than CUR, particularly when bound to LPS, with binding energies of −8.7 and −8.3 kcal/mol, respectively. However, better in silico affinity did not always translate into improved cellular effects. These findings indicate that metabolic context significantly influences CUR’s biological activity and that forming a zinc complex offers a safer, more reliable profile. This positions Zn–CUR as a candidate warranting further investigation for TNBC, particularly in the context of hyperglycemia.