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Investigating Keap1 Protein Interactions to Uncover New Therapeutic Strategies

Investigating Keap1 Protein Interactions to Uncover New Therapeutic Strategies

Structure of the Keap1 protein predicted using the AlphaFold3 server

Category
Projekti Hrvatske zaklade za znanost
Total cost
199.985,00
EUR
Start date
Dec 5th 2025
End date
Dec 4th 2028
Status
Active
More information
Project Web page

Principal investigator

Antonija Tomić, dr. sc.

Antonija.Tomic@irb.hr

+385 1 457 1251

The Keap1 protein primarily acts as a repressor of Nrf2, serving as a crucial component of the Keap1–Nrf2 signaling pathway, which is the primary regulator of oxidative and electrophilic stress response in the cell. While the activation of Nrf2 protects normal cells from various toxic agents and diseases, overactivation of Nrf2 has been linked to cancer progression and resistance to chemotherapy and radiotherapy, making Keap1 an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions. In addition to protecting cancer cells from oxidative damage, persistent Nrf2 activation has also been found to significantly impact cell mobility and metastasis, facilitating cell migration and invasion. In this project, we aim to explore the role of interactions between Keap1 and DPP III and actin proteins, respectively, which under specific conditions have been correlated with cancer development and tumor metastasis. Both proteins have been found to engage in interactions with the Kelch domain of the Keap1 protein. Specifically, studies on lung and breast cancer cell lines have suggested that the overexpressed DPP III protein competes with Nrf2 for Keap1 binding, resulting in Nrf2 translocation to the nucleus and expression of antioxidant genes. Hence, our objective is to identify a molecule that could inhibit the moonlighting activity of DPP III in the Keap1–Nrf2 pathway, indirectly enhancing the interaction between Keap1 and Nrf2, thereby suppressing Nrf2-induced gene expression in cancer cells. By directly binding to actin, Keap1 participates in regulating cytoskeletal dynamics and functions. Disrupting actin filaments can disturb the Nrf2–Keap1 interaction, promoting Nrf2 activation. Investigation of the Keap1-actin interaction could shed light on the potential role of Keap1 in actin cytoskeleton dynamics and cell migration, offering insights into novel therapeutic strategies for diseases associated with oxidative stress.