Fermented NaDES–Ginger Extract Attenuates Hyperglycemia-Driven Inflammation and Endothelial Adhesion in Colorectal Cancer Through the NF-κB/COX-2 Axis

Hyperglycemia aggravates colorectal cancer (CRC) progression by driving inflammatory pathways and facilitating tumor–endothelial cell adhesion. Ginger extract exhibits well-known anti-inflammatory properties; however, its pharmacological efficacy under such metabolic stress conditions remains largely unclear. In this study, the effects of a fermented ginger extract prepared using natural deep eutectic solvents (FNGE) were examined on high-glucose-induced pathogenesis in human CRC cells. DLD-1 cells were exposed to high-glucose conditions with or without FNGE treatment. The expression of inflammatory mediators (cyclooxygenase-2 [COX-2], prostaglandin E2 [PGE2], interleukin [IL-6], and IL-8), the adhesion capacity of CRC cells to human umbilical vein endothelial cells (HUVECs), and activation of the NF-κB signaling pathway were examined. FNGE treatment significantly and dose-dependently attenuated the high-glucose-induced upregulation of COX-2 mRNA and PGE2 secretion, while concurrently suppressing the expression of IL-6 and IL-8. Furthermore, FNGE pretreatment markedly impaired CRC cell adhesion to HUVECs. Mechanistic analyses, including targeted COX-2 knockdown and pharmacological inhibition, revealed that FNGE exerts its anti-inflammatory and anti-adhesive effects primarily through the suppression of NF-κB activation, a master transcriptional regulator of these pathogenic pathways. These in vitro findings demonstrated that FNGE effectively mitigates high glucose-mediated inflammation and endothelial adhesion in CRC cells by downregulating the NF-κB/COX-2 signaling axis. Thus, this study provides a preliminary biochemical basis for the potential application of green-extracted phytochemicals under metabolic stress, highlighting the need for future in vivo validation to confirm their translational relevance.