Thioredoxin-interacting protein (TXNIP) has multiple disease-associated functions including inducing oxidative stress by inhibiting the anti-oxidant and thiol reducing activity of thioredoxin (TRX), reducing cellular glucose transport, and is a component of the activated inflammasome complex. Increased expression of TXNIP is encountered in diabetic conditions of high glucose. Curcumin and chemical derivatives have multiple therapeutic properties as anti-inflammatories, anti-oxidants, amyloid aggregation inhibitors and modulate a number of cellular signaling pathways. Using a fluorinated-derivative of curcumin (designated Shiga-Y6), we showed significant inhibition of TXNIP mRNA and protein expression, and induction of TRX mRNA and protein in ARPE-19 retinal pigment epithelial cells and THP-1-derived macrophages, while the non-fluorinated structural equivalent (Shiga-Y52) and native curcumin did not show these same effects. Shiga-Y6 was effective in reducing high glucose, endoplasmic reticulum stress-induced TXNIP in ARPE-19 cells, and reducing lipopolysaccharide and endoplasmic stress-induced proinflammatory gene expression in THP-1 macrophages. Moreover, TXNIP-knockdown experiments showed that the anti-inflammatory effect of Shiga-Y6 in LPS-stimulated THP-1 macrophages was TXNIP-independent.