Roles of NRF2 in Fibrotic Diseases: From Mechanisms to Therapeutic Approaches

Abstract

Fibrosis is a persistent inflammatory response that causes scarring and tissue sclerosis by stimulating myofibroblasts to create significant quantities of extracellular matrix protein deposits in the tissue. Oxidative stress has also been linked to the development of fibrosis in several studies. The nuclear erythroid 2-related factor 2 (NRF2) transcription factor controls the expression of several detoxification and antioxidant genes. By binding to antioxidant response elements, NRF2 is activated by oxidative or electrophilic stress and promotes its target genes, resulting in a protective effect on cells. NRF2 is essential for cell survival under oxidative stress conditions. This review describes Kelch-like epichlorohydrin-associated protein 1 (KEAP1)/NRF2 signaling mechanisms and presents recent research advances regarding NRF2 and its involvement in primary fibrotic lesions such as pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, and renal fibrosis. The related antioxidant substances and drugs are described, along with the mechanisms by which KEAP1/NRF2 regulation positively affects the therapeutic response. Finally, the therapeutic prospects and potential value of NRF2 in fibrosis are summarized. Further studies on NRF2 may provide novel therapeutic approaches for fibrosis.

Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats

“…Moreover, cells and tissues are damaged when the oxidative stress caused by ROS exceeds the body's defenses. 33 The results of this study demonstrated that severe oxidative stress to the liver of CRS rats inhibited Nrf2 nuclear transfer. In this study, brusatol could significantly reverse the protective effect of LYC, increase ROS levels and MDA content, and aggravate hepatic oxidative stress.…”

“…GSH, SOD, and CAT constitute the antioxidant defense system in organisms and play a key role in scavenging oxygen-free radicals and peroxides. Moreover, cells and tissues are damaged when the oxidative stress caused by ROS exceeds the body’s defenses . The results of this study demonstrated that severe oxidative stress to the liver of CRS rats inhibited Nrf2 nuclear transfer.…”

Fibroblast Nrf2 inhibits profibrotic transcription with Ddx54 and mitigates pathological fibrosis in the mouse heart and kidney

“…Although the antifibrotic effect of Nrf2 has been observed previously, it has been assumed that Nrf2 primarily suppresses oxidative stress via the expression of antioxidant genes such as GSTs, HO-1, and NQO1, and the consequent inhibition of ROS injury or signaling contributes to antifibrosis 47 . In contrast, we discovered that Nrf2 directly regulates the transcription of profibrotic genes independently of ROS scavenging, at least in the context of fibroblast activation.…”

Capsaicin ameliorate pulmonary fibrosis via antioxidant Nrf-2/ PPAR- γ pathway activation and inflammatory TGF-β1/ NF-κB/COX II pathway inhibition

“…Additionally, activated inflammatory cells produce ROS, which, in turn, recruit other inflammatory cells and amplifying the damage ( Nathan, 2003 ). Nuclear factor erythroid 2–related factor 2 (Nrf-2) is a master regulator of cellular resistance to oxidative stress via modulation of the expression of genes encoding antioxidant enzymes and genes controlling immune and inflammatory responses, tissue remodeling and fibrosis ( Hao et al, 2022 ). Alterations in the redox state activate Nrf2 which upregulates the production of antioxidant, xenobiotic-metabolizing, and cytoprotective enzymes, safeguarding cells against ROS ( Chan and Kan, 1999 ).…”