ML385, a selective inhibitor of Nrf2, demonstrates efficacy in the treatment of adult T-cell leukemia.

Abstract

Nrf2 plays a critical role in regulating cytoprotective transcriptional responses and glucose metabolism while also preventing inflammation-induced carcinogenesis. However, Nrf2 can paradoxically promote carcinogenesis. Here, we aimed to elucidate the role of Nrf2 in ATL associated with HTLV-1. HTLV-1-infected T-cell lines exhibited nuclear accumulation of Nrf2. Nrf2 knockdown along with the inhibition of its activity using ML385, decreased cell proliferation and survival. Furthermore, ML385-induced G1 arrest by enhancing γH2AX and p53 expression while downregulating CDK4/6, cyclin D2/E, and c-Myc. Additionally, ML385 triggered caspase-mediated apoptosis by downregulating the expression of anti-apoptotic proteins while upregulating pro-apoptotic proteins. The compound also induced necroptosis, promoted JNK phosphorylation, and inhibited the NF-κB, AP-1, and STAT3/5 signaling. Moreover, ML385 was found to reduce the expression of LDHA, glucose uptake, and the levels of lactate derived from glycolysis. Overall, these results suggest that Nrf2 functions as an oncogene in ATL and may represent a promising therapeutic target.