TY - JOUR
T1 - NRF2 activation in cancer and overview of NRF2 small molecule inhibitors
AU - Ngo, Hoang Hai
AU - Yu, Bo Yeong
AU - Lee, Jeong Eun
AU - Kim, Hyunwoo
AU - Keum, Young Sam
N1 - Publisher Copyright:
© The Pharmaceutical Society of Korea 2025.
PY - 2025/8
Y1 - 2025/8
N2 - NRF2 is a redox-sensitive transcription factor that activates the expression of phase II detoxifying and antioxidant enzymes. In addition to maintaining redox homeostasis, NRF2 regulates various other processes, including metabolism, stem cell renewal, mitochondrial function, and proteostasis. NRF2 is considered a tumor suppressor because its activation by chemopreventive phytochemicals contributes to the detoxification of oxidants and electrophiles in normal cells. However, aberrant NRF2 activation occurs in cancer due to mutations in the KEAP1/NRF2 pathway, and it contributes to the generation of a tumor microenvironment that favors the proliferation, survival, and chemoresistance of cancer cells. In this review, we present the regulatory mechanisms of NRF2 and discuss how NRF2 activation contributes to chemoresistance. We also explain therapeutic strategies that exploit the vulnerabilities of NRF2-addicted cancer cells, providing NRF2 small-molecule inhibitors along with their mechanisms of action.
AB - NRF2 is a redox-sensitive transcription factor that activates the expression of phase II detoxifying and antioxidant enzymes. In addition to maintaining redox homeostasis, NRF2 regulates various other processes, including metabolism, stem cell renewal, mitochondrial function, and proteostasis. NRF2 is considered a tumor suppressor because its activation by chemopreventive phytochemicals contributes to the detoxification of oxidants and electrophiles in normal cells. However, aberrant NRF2 activation occurs in cancer due to mutations in the KEAP1/NRF2 pathway, and it contributes to the generation of a tumor microenvironment that favors the proliferation, survival, and chemoresistance of cancer cells. In this review, we present the regulatory mechanisms of NRF2 and discuss how NRF2 activation contributes to chemoresistance. We also explain therapeutic strategies that exploit the vulnerabilities of NRF2-addicted cancer cells, providing NRF2 small-molecule inhibitors along with their mechanisms of action.
KW - NRF2 small molecule inhibitors
KW - Nuclear factor erythroid 2-related factor 2 (NRF2)
UR - https://www.scopus.com/pages/publications/105013332537
U2 - 10.1007/s12272-025-01557-x
DO - 10.1007/s12272-025-01557-x
M3 - Review article
C2 - 40815486
AN - SCOPUS:105013332537
SN - 0253-6269
VL - 48
SP - 676
EP - 705
JO - Archives of Pharmacal Research
JF - Archives of Pharmacal Research
IS - 7-8
ER -
