6-Gingerol alleviates high glucose-induced inflammation and cytotoxicity in THP-1 cells by inhibiting TLR4 signaling.

High glucose (HG) conditions contribute to inflammation, oxidative stress, and DNA damage in monocytes, thereby promoting chronic disease progression. This study examines the protective effects of 6-gingerol, a major bioactive compound in ginger, against HG-induced cellular dysfunction in THP-1 monocytes. Treatment with 6-gingerol at concentrations of 30 and 60 µM significantly reduced the expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) at both the protein and mRNA levels, as demonstrated by Western blotting, qPCR, and ELISA. The compound also inhibited the activation of TLR2/4-mediated signaling pathways, including NF-κB, JAK/STAT3, and MAPK. Moreover, 6-gingerol mitigated HG-induced DNA damage by restoring phosphorylated levels of ATM, ATR, BRCA1, and p53 and normalized cell cycle regulation by modulating the expression of CDK4, Cyclin D1/E, and p21/p27. Cell viability assays (CCK-8, WST-1, and LDH) and FACS analyses (CFSE and Annexin V) confirmed no cytotoxic effects at 60 µM, suggesting that 6-gingerol offers protection without inducing cell death. A supplementary comparison with TLR4 inhibitors revealed a shared mechanism of action, further supporting the involvement of TLR4 in HG-induced pathogenesis. Collectively, these findings support 6-gingerol as a promising anti-inflammatory and cytoprotective agent under diabetic-like stress conditions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-34192-z.