PEPTIDE IDR-1002 REGULATES THE ANTIOXIDANT AND ANTI-INFLAMMATORY RESPONSES BY ACTIVATING THE KEAP1-NRF2 SIGNALING PATHWAY
IDR-1002 shows promise in activating the Nrf2 antioxidant response and reducing inflammation in endothelial cells, but its clinical relevance in humans is not established.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
The study investigated the peptide IDR-1002 for its ability to activate the Nrf2-mediated antioxidant response and mitigate inflammation in endothelial cells. It was tested in HEK293 and bovine endothelial cells, with an EC50 of 18.57 μM for transcriptional activity. The results indicated a significant reduction in reactive oxygen species and TNF-α expression in stimulated cells.
Abstract
Background Oxidative stress and inflammation are mutually reinforcing physiological processes. The transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) acts as the master regulator of redox homeostasis and anti-inflammatory signaling. To overcome the off-target limitations of conventional electrophilic Nrf2 activators, this study investigates selective peptide-based modulators. We present data indicating that an innate defense regulator (IDR)-1002 peptide is able to activate the Nrf2-mediated antioxidant response and mitigate inflammation in an endothelial cell model. Methods We first screened several IDR peptides IDR-1 (Lys-Ser-Arg-Ile-Val-Pro-Ala-Ile-Pro-Val-Ser-Leu-Leu), IDR-1018 (Val-Arg-Leu-Ile-Val-Ala-Val-Arg-Ile-Trp-Arg-Arg), HH2 (Val-Gln-Leu-Arg-Ile-Arg-Val-Ala-Val-Ile-Arg-Ala) and IDR-1002 (Val-Gln-Arg-Trp-Leu-Ile-Val-Trp-Arg-Ile-Arg-Lys) for their ability to induce Nrf2 nuclear translocation in HEK293 and bovine endothelial cells (BEC) via Western blot and ELISA. Transcriptional activity was assessed in HepG2 cells using an ARE (Antioxidant Response Element)-luciferase reporter assay to determine the EC 50 . Downstream expression of antioxidant enzymes, including HO-1 (Heme Oxygenase-1), NQO1 (NAD(P)H:quinone oxidoreductase 1), and GCLM (Glutamate-Cysteine Ligase Modifier Subunit), was quantified by ELISA. GST (Glutathione S-Transferase) activity induced by IDR-1002 was measured using a CDNB-GSH conjugation assay. Finally, the functional capacity to reduce H 2 O 2 -induced ROS (Reactive Oxygen Species) and TNF-stimulated inflammation was measured in BECs. Results Among the tested peptides, IDR-1002 induced the most potent concentration-dependent nuclear translocation of Nrf2 in both cell lines. IDR-1002 activated ARE-dependent transcription with an EC 50 of 18.57 μM. This activation led to a significant time-dependent increase in HO-1, NQO1, and GCLM protein levels, alongside enhanced GST activity. Functionally, IDR-1002 pretreatment resulted in a dose-dependent reduction of intracellular reactive oxygen species (ROS) production (up to 5.4-fold at 50 μM) and a significant decrease in TNF-α expression in stimulated BECs. Conclusions IDR-1002 acts as a distinct dual-function regulator that simultaneously modulates the Nrf2 antioxidant response and inhibits NF-κB-mediated inflammation. These findings highlight the potential of IDR-1002 as a promising molecular template for the design of new therapeutic approaches against chronic diseases characterized by the interplay between oxidative stress and inflammation.