Nrf2 inhibitor Brusatol inhibited the activation of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1) caused by esculetin and abolished its protection effect. Esculetin protected cerebral neurons from ischemia-reperfusion injury by inhibiting NF-κB and Nrf2/HO-1/NQO-1 activation.

P1, N=12, Recruiting, Reata, a wholly owned subsidiary of Biogen | Not yet recruiting --> Recruiting

P2, N=53, Completed, EpicentRx, Inc. | Phase classification: P2a --> P2

P3, N=292, Active, not recruiting, EpicentRx, Inc. | Recruiting --> Active, not recruiting

P=N/A, N=20, Recruiting, Reata, a wholly owned subsidiary of Biogen | Not yet recruiting --> Recruiting

Moreover, there was an elevation in the activity of anti-oxidative enzymes, specifically SOD and GSH (P<0.05), coupled with an enhanced expression of Nrf2 and HO-1 in the diabetic group (P<0.01). The study findings demonstrate that TFST can suppress oxidative stress by modulating the Nrf2 pathway and up-regulating HO-1 activity, thereby ameliorating diabetes-induced acute lung injury.

P=N/A, N=20, Not yet recruiting, Reata, a wholly owned subsidiary of Biogen

Additionally, the suppression of ALDH2 on IL-6 and TNF-α levels and promotion of it on OCN and RUNX2 expression in PDLSC model of periodontitis was further intensified by ferrostatin-1, but reversed by FIN56. ALDH2 may alleviate inflammation and facilitate osteogenic differentiation of PDLSC in periodontitis by hindering ferroptosis via activating Nrf2, suggesting it to be a promising candidate for treating periodontitis.

Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.

P=N/A, N=300, Not yet recruiting, Reata, a wholly owned subsidiary of Biogen

P=N/A, N=10500, Active, not recruiting, Biogen | Not yet recruiting --> Active, not recruiting

P1, N=12, Not yet recruiting, Reata, a wholly owned subsidiary of Biogen

P1/2, N=52, Active, not recruiting, Golden Biotechnology Corporation | Trial completion date: Mar 2024 --> Dec 2024

Praelolide markedly alleviated synovial inflammation and bone destruction in CIA mice by enhancing catalase activity and activating the Nrf2 pathway to reduce disease-related ROS accumulation, highlighting praelolide as a promising candidate for multitarget treatment of RA.

P3, N=102, Completed, Biogen | Recruiting --> Completed

We verified that the anti-inflammatory effect of Lico A is associated with the activation of the Nrf2/HO-1 axis. These results indicated that Lico A could provide a protective role in A. fumigatus keratitis through its anti-inflammatory and antifungal activities.

In summary, our findings suggest that bufalin exerts anti-inflammatory and antioxidant actions in NaT-SAP rats by inhibiting NF-κB and activating the Keap1-Nrf2/HO-1 pathway. This study represents the inaugural application of bufalin in NaT-induced SAP rats, indicating its potential as an effective therapeutic agent for SAP patients.

4-HC treatment significantly decreased lung oxidative stress, inflammatory cell infiltration, and IgE levels. According to our findings, we imply that 4-HC may be utilized as an anti-asthmatic agent through the upregulation of Nrf2/GPx4 signaling pathway.

Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD+, resulting in depletion of both NAD+/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action.

This suggests that it has the potential to be used as a therapeutic agent for reducing dental pulp inflammation. These findings support the need to further explore Asiatic acid as a promising intervention for maintaining dental pulp health.

Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.

Finally, the review examines potential therapeutic strategies targeting NINJ1 for improved MS management. Abbreviations: MS, Multiple sclerosis; CNS, Central nervous system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma membrane rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated molecular patterns; PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis factor; APCs, Antigen-presenting cells; ECs, Endothelial cells; TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear cells; FACS, Fluorescence-activated cell sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T cell receptor; ROS, Reactive oxygen species; AP-1, Activator protein-1; ANG1, Angiopoietin 1; BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related protein 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase 1; PAK1, p21-activated kinases 1; Rac1, Ras-related C3 botulinum toxin substrate 1; β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TLR4, Toll-like receptor 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor associated factor 6; TAB2/3, TAK1 binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; JNK, c-Jun N-terminal kinase; ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; AP-1, activator protein-1; ASC, Apoptosis-associated Speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NLRP3, Pyrin domain-containing 3; CREB, cAMP response element-binding protein.

In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of MET. In conclusion, this study suggested that MET attenuated chronic hypoxia-induced WMI through activating the NRF2/HO-1/NF-κB pathway, indicating that MET might be a promising therapeutic option for WMI.

P1/2, N=25, Completed, AnnJi Pharmaceutical Co., Ltd. | Active, not recruiting --> Completed

In conclusion, DDX5 deficiency triggers Wnt/β-catenin signaling, promoting p52/RelB and NRF2 activation, thereby enabling ferroptosis evasion upon sorafenib treatment. Similarly, independent of sorafenib, DDX5 deficiency in liver tumors enhances activation and gene expression of these interconnected pathways, underscoring the clinical relevance of DDX5 deficiency in HCC progression and therapeutic response.

In summary, our data have confirmed that Met has a positive effect on flap survival and reduces necrosis. The mechanism of action involves the regulation of the Nrf2/HO-1 signaling pathway to combat oxidative stress and reduce damage.

All the results highlighted the anti-rheumatic potential of MAE in RA in-vitro and in-vivo by inhibiting the TLR4/NF-кB/COX-2/iNOS and promoting the Nrf2/HO-1 signaling axis.

These findings suggest that Nes-1 might be used as a promising agent for the prevention of CA.

These results suggest that MF has anti-neuroinflammatory effects via inhibiting NF-κB signaling by activating Nrf2-ARE. These studies support that MF could be a strong candidate drug for treating and or preventing TS-induced neuroinflammation and ischemic stroke.

P1, N=2, Terminated, EpicentRx, Inc. | N=24 --> 2 | Trial completion date: Dec 2024 --> Jul 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2024; Low Enrollment

Mechanically, REO relieved oxidative stress via activating the Nrf2 signaling pathway and enhancing the protein expression of Nrf2, NQO-1, and HO-1, which was further verified by molecular docking between the main component 1.8-cineole and the Kelch domain of KEAP1. Therefore, REO could be considered as a potent natural antioxidant with a potential strategy in the food and pharmaceutical industries.

In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.

The expression of EGR1 is downregulated in BC, which is correlated with poor prognosis of BC patients. EGR1 suppresses the proliferation of BC cells and facilitates erastin-induced ferroptosis by activating Nrf2-HMOX1 signaling pathway in BC cells.

However, upon reexpressing Keap1 in Keap1 KO cells, the ability of sesamolin to elevate Nrf2 protein expression was restored, highlighting the crucial role of Keap1 in sesamolin-induced Nrf2 activation. Taken together, these findings show that sesamolin can inhibit adipocyte differentiation through Keap1-mediated Nrf2 activation.

P1, N=20, Recruiting, Reata, a wholly owned subsidiary of Biogen | Not yet recruiting --> Recruiting

Aucubin alleviates inflammation, oxidative stress, apoptosis, and pulmonary fibrosis in COPD mice and CSE-treated MLE12 cells by activating the Nrf2/HO-1 signaling pathway.

The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-β and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.

P2, N=60, Recruiting, Assistance Publique - Hôpitaux de Paris | Trial completion date: Oct 2026 --> Oct 2027 | Trial primary completion date: Feb 2024 --> Oct 2025

Treatment with DMF effectively reversed these changes, alleviating oxidative stress by activating the Keap1-Nrf2/HO-1 signaling pathway, ultimately conferring protection against AKI. Activating Keap1-Nrf2/HO-1 signaling pathway may be a potential therapeutic strategy for attenuating oxidative stress-induced AKI after TBI.

P1, N=20, Not yet recruiting, Reata, a wholly owned subsidiary of Biogen | Trial completion date: Feb 2024 --> Feb 2030 | Initiation date: Nov 2023 --> Jul 2024 | Trial primary completion date: Feb 2024 --> Feb 2030

Current chemotherapy for CAC, based on 5-fluorouracil and oxalipltin, is not fully effective and displays severe side effects, prompting the search for alternative therapies...Low-dose (DMF30) and high-dose of DMF (DMF100) or oxaliplatin (OXA) were administered from the 8th to 12th week of the experiment, and then the colon tissues were analysed histologically and biochemically...DMF had a dual effect on CAC. At low dose, DMF is chemotherapeutic and acts as an antioxidant and immunomodulator, whereas at high dose, DMF is pro-oxidant and exacerbates colitis-associated cancer.

To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it...In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.