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.

Taken together, our work uncovers a new mechanism by which ShtIX induced ferroptosis through inhibition the Nrf2 pathway and activation of NCOA4-mediated ferritinophagy in NSCLC cells. Targeting ferritinophagy to regulate ferroptosis offers a novel therapeutic strategy for the treatment of lung cancer with ShtIX.

In vivo, ML385 also promoted the killing effect of radiation on xenografted tumours in nude mice. This study identifies NRF2 inhibitor ML385 as a radiosensitizer of ESCC, which highlights the therapeutic potential of the NRF2-SLC7A11 pathway and provides a deeper understanding of the mechanism of ferroptosis in esophageal squamous cell carcinoma.

In this investigation, the treatment with solasodine and doxorubicin combination showed a notable increase in intracellular ROS generation in KBChR-8-5 cells...Additionally, the combination therapy increased the lipid peroxidation levels while simultaneously reducing the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the levels of glutathione (GSH). These results demonstrated that solasodine disrupts redox balance, and overcomes drug resistance by downregulating P-gp via regulating Nrf2/Keap1 signaling pathway in MDR cancer cells.

In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol...Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.

It is demonstrated that EZ@TD synergistically inhibited tumor growth and activated the antitumor immune response by inhibiting the Nrf2/ARE signaling pathway in tumors. We provide a new paradigm for amplifying intracellular oxidative stress by interfering with various signaling pathways.

Additionally, the expression of NRF2-regulated antioxidant and detoxification genes including SOD2, HMOX2, and GSS was maintained upon ML-385 treatment. In conclusion, our results demonstrated that all the studied inhibitors, namely K67, retinoic acid, and ML-385, increased the efficacy of doxorubicin in doxorubicin-resistant HL-60/DR cells, and suggested a potential strategy of combination therapy using NRF2 inhibitors and doxorubicin in overcoming doxorubicin resistance in leukemia.

Our study shows that HIP1 depletion leads to activation of various molecular pathways responsible for cell proliferation and survival. Additionally, enhancement of invasion and anchorage-independent growth in HIP1 depleted subsets of NSCLC cells is via upregulation of NRF2 and can be reversed by its inhibitor.

Our study demonstrated that AKR1B1 resisted RSL3-induced ferroptosis by regulating GPX4, PTGS2 and ACSL4, which was further demonstrated in a xenograft nude mouse model. Our work reveals a critical role for the AKR1B1 in the resistance to RSL3-induced ferroptosis in gastric cancer.

The ability of colony formation and migration of T-HaCaT cells decreased. In conclusion, arsenite activated NRF2 in the later stages, decreasing apoptosis characterized by inhibiting endoplasmic reticulum stress-depended and mitochondria-depended apoptosis pathway, and further promoting NaAsO2-induced HaCaT cellular malignant transformation.

In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.

Additionally, we examined changes in the expression of cell-cycle-related proteins and found that ML385 induced cell cycle arrest at the G1/S phase in HNSCC cell lines. Our findings suggest that ML385 can regulate cell cycle progression, inhibit HNSCC growth, and have potential as a therapeutic agent for HNSCC.

We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations.

Juglone induces ferroptosis and inhibits the growth of GBM by targeting the Nrf2/Gpx4 signaling pathway and thus holds promise as a novel ferroptosis inducer or anti-GBM drug.

Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.

By contrast, NRF2 overexpression or administration of the reactive oxygen species inhibitor N-acetylcysteine and vitamin E could effectively suppress the anti-AML effects of ML385+venetoclax. Furthermore, the ferroptosis inducer erastin increased the anti-AML effects of venetoclax. Our study demonstrated that NRF2 inhibition could enhance the AML cell death induced by venetoclax via the ferroptosis pathway. Thus, the combination of ML385 with venetoclax may offer a favorable strategy for AML treatment.

To assess the interplay between NRF2 and dysfunctional p53, genetic targeting of p53 showed reduced activation of the NRF2 pathway in response to the lower dose of Ru‑bdcurc, increasing the cell death. These findings identified for the first time a possible dysfunctional p53/NRF2 interplay in BON‑1 cell line that can be a novel key determinant in cell resistance to cytotoxic agents to be evaluated also in GEP‑NEN.

Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.

Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

In a tumor xenograft model, this combination treatment markedly inhibited renal tumor growth in vivo; and it is associated with decreased expression of Rubicon, p62, HO-1 and vessel density in the tumor tissues. Together, cabozantinib + Honokiol combination can significantly inhibit c-Met-induced and Nrf2-mediated anti-oxidant pathway in renal cancer cells to promote increased oxidative stress and tumor cell death.

Knockdown of Nrf2 in SH-SY5Y cells increased 1-BP-induced reactive oxygen species production and cell apoptosis, and inhibited HO-1 and Bcl-2 protein expression, while overexpression of Nrf2 alleviated these processes. These findings suggest that 1-BP-induced oxidative stress and apoptosis in SH-SY5Y cells are associated with Nrf2 function inhibition.

Suppression of Nrf2 by siRNA showed a reduced expression of lipogenic genes, ablation of lipid droplets, decrease in the number of apoptotic cells, and restoration of insulin secretion with a corresponding increase of Pdx1, BETA2, and Ins1 gene expression. Our study thus suggested an important aspect of lipid accumulation in the pancreatic β-cells contributing to β-cell dysfunction and demonstrated the role of Fetuin-A in CD36 expression, with a possible way of restoring β-cell function by targeting Nrf2.

We developed a BRET-based biosensor system to detect the KEAP1/NRF2 interaction and classify KEAP1 mutations. This strategy would identify drug-resistant KEAP1 somatic mutations in clinical molecular profiling of tumors.

By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

Moreover, we show that mice lacking the Nrf2 gene show increased clinical signs of disease and lung pathology when infected with a mouse-adapted strain of SARS-CoV-2. Overall, this study provides a mechanistic explanation for the observed unbalanced pro-oxidative response in SARS-CoV-2 infections and suggests that therapeutic strategies for COVID-19 may consider the use of pharmacologic agents that are known to boost the expression levels of cellular NRF2.

However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.

Our results suggest that BRU could be a potential pharmacological agent for the therapeutic approach of CLL, in monotherapy and as an adjuvant to treatment with IBR. Chronic lymphocytic leukemia, Apoptosis, ibrutinib, Transcription factor

N1S treatment decreases the transcription of Nrf2-dependent genes and sensitizes Nrf2-dependent cancer cells to cisplatin. Overall, N1S is a promising lead for the sensitization of Nrf2-addicted cancers.

These results show that wogonin could significantly reduces pancreatic cancer cell proliferation and induce ferroptosis via the Nrf2/GPX4 axis. Therefore, wogonin could be potentially used for treating patients with pancreatic cancer.

Neuroprotective effects of paeoniflorin in MPTP-induced PD mice may be mediated via inhibition of oxidative stress and apoptosis of dopaminergic neurons in substantia nigra through activation of the Nrf2/HO-1 signaling pathway.

Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment of AML patients carrying a DNMT3A R882H mutation.

The findings reveal that BiP and NRF2 interconnection was a key regulator of colon cancer cells resistance to Ru-bdcurc cytotoxic effect. Targeting that interconnection overcame the protective mechanism and enhanced the antitumor effect of the Ru-bdcurc compound.

In line with this, the miR-181a-2-3p inhibitor transfection could increase tumorigenicity of NRF2-silenced colorectal cancer cells. Collectively, our study suggests the involvement of NRF2/miR181a-2-3p signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments.

Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth...The authors found that brusatol, as a natural compound, suppresses progestin metabolism through regulating the NRF2-TET1-AKR1C1 pathway to sensitize precancerous/endometrial cancers to progestin and relieve progestin resistance. This study indicates that progestin combined with brusatol may enhance the treatment effects and that AKR1C1 expression patterns may serve as an important biomarker of progestin resistance in endometrial cancer.

As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated.

Mechanisms underlying tamoxifen-induced radioresistance are linked to cellular adaptations to persistently increased ROS levels, leading to cells with chronically upregulated antioxidant capacity and glycolysis. Pharmacological inhibition of antioxidant responses re-sensitizes breast cancer cells to irradiation.

There were no significant differences in mouse body weight or liver and kidney function among the four groups. In summary, CPT is a Nrf2 inhibitor that could enhance the efficacy of sorafenib against HCC.

Concordantly, NRF2 levels correlate with HERC2 and VAMP8 in human ovarian cancer tissues, as well as ferroptosis resistance in a panel of ovarian cancer cell lines. Last, the feasibility of inhibiting NRF2 to increase the LIP and kill cancer cells via ferroptosis was demonstrated in preclinical models, signifying the impact of NRF2 inhibition in cancer treatment.

Our findings imply that tiliroside is a potent TBK1 inhibitor and a candidate natural anti-cancer product that could function as a sensitizer of sorafenib in HCC treatment by targeting TBK1 to induce ferroptosis.

Based on these findings we predicted and confirmed that NRF2 inhibition increased sensitivity to vincristine in a long-term 3D drug treatment assay of Group 3 MB. Thus, by combining scRNAseq and 3D OrbiSIMS in a relevant model system we were able to define MB subgroup heterogeneity at the single cell level and elucidate new druggable biomarkers for aggressive Group 3 and low-risk SHH MB.