Keap1-Nrf2

Loganic acid is an iridoid isolated from cornelian cherry fruits. Loganic acid inhibits NF-κB signaling pathway, activates Nrf2 signaling pathway, exhibits anti-inflammatory activity. Loganic acid can modulate diet-induced atherosclerosis and redox status. Loganic acid has strong free radical scavenging activity and remarkable cyto-protective effect against heavy metal mediated toxicity. Loganic acid is orally active.

Jujuboside B is a bioactive saponin component isolated from Ziziphi Spinosae Semen (sour jujube seed), with oral efficacy and blood-brain barrier permeability. Jujuboside B induces acute leukemia cell death and drives necroptosis apoptosis by activating the RIPK1/RIPK3/MLKL pathway. Jujuboside B upregulates the expression of NOXA, PARP and caspase-3, activates AMPK, inhibits the proliferation of breast cancer cells, and induces cell apoptosis and autophagy. Jujuboside B inhibits angiogenesis and tumor growth by blocking the VEGFR-2 signaling pathway. Jujuboside B alleviates liver injury in mice by regulating the Nrf2-STING signaling pathway. Jujuboside B alleviates liver injury by regulating anti-inflammatory responses and downregulating the expression of 11β-HSD2. Jujuboside B induces ferroptosis and overcomes radioresistance in non-small cell lung cancer via the PPARγ-ATF3-Gpx4 signaling pathway. Jujuboside B exerts inhibitory effects on platelet aggregation. Jujuboside B inhibits febrile seizures by suppressing the activity of AMPA receptors. Jujuboside B reverses chronic unpredictable mild stress-promoted tumor progression by blocking the PI3K/Akt and MAPK/ERK pathways and dephosphorylating CREB signaling. Jujuboside B is applicable to related studies on acute leukemia, breast cancer, PM_2.5-induced lung injury, hepatotoxicity, liver injury, colorectal cancer, non-small cell lung cancer, thromboembolic diseases, cardiovascular diseases associated with high platelet aggregation, febrile seizures, and depressive-like phenotypes.

3',4'-Dihydroxyacetophenone (3,4-DHAP) is a phenolic compound with oral bioavailability, possessing potent antioxidant, anti-inflammatory, anticancer and cardiovascular protective activities. 3',4'-Dihydroxyacetophenone inhibits mushroom Tyrosinase activity with an IC₅₀ of 10 μM, thereby suppressing melanogenesis. 3',4'-Dihydroxyacetophenone inhibits platelet aggregation in platelet-rich plasma. 3',4'-Dihydroxyacetophenone reduces ROS levels in human umbilical vein endothelial cells treated with high glucose, upregulates the expression of Nrf2, HO-1 and PARP-1 in cells, and promotes the nuclear translocation of Nrf2. 3',4'-Dihydroxyacetophenone induces autophagy and apoptosis. 3',4'-Dihydroxyacetophenone inhibits seed germination/growth in most plants. 3',4'-Dihydroxyacetophenone can be used in the research of cancer, neurodegenerative diseases, non-alcoholic steatohepatitis, diabetes, obesity, skin pigmentation disorders, and cardiovascular and cerebrovascular diseases.

Gypenoside XLIX is a multifunctional bioactive compound that can be isolated from Gynostemma pentaphyllum, with a K_a value of 1.58 μM for its binding to SIRT1. Gypenoside XLIX acts as a PPAR-α agonist. It inhibits the activation of TLR4-mediated NF-κB signaling pathway by activating the Sirt1/Nrf2 signaling pathway, reduces ROS accumulation, and alleviates hepatic inflammatory injury in mice with sepsis-induced liver disease. Gypenoside XLIX targets SIRT1 to block YAP-NLRP3 activation and improve sepsis-induced cardiomyopathy. Gypenoside XLIX inhibits apoptosis (Apoptosis), pyroptosis (Pyroptosis), autophagy (Autophagy), lipid peroxidation, pro-inflammatory cytokines and anti-inflammatory cytokines. Gypenoside XLIX alleviates sepsis-induced splenic injury by inhibiting inflammation and oxidative stress, and mitigates sepsis-associated encephalopathy by targeting PPAR-α. Gypenoside XLIX prevents acute kidney injury by inhibiting IGFBP7/IGF1R-mediated programmed cell death and inflammation. Gypenoside XLIX inhibits the expression and activity of vascular cell adhesion molecule-1 in cytokine-induced human endothelial cells. Gypenoside XLIX is applicable to research related to acute liver injury, lung injury, cardiomyopathy, acute splenic injury, sepsis-associated encephalopathy, acute kidney injury, atherosclerosis and chronic inflammation.

Swertiamarin is an orally active natural product with hypoglycemic, lipid-lowering, anti-rheumatic, and antioxidant activities. Swertiamarin can regulate the levels of pro-inflammatory cytokines, MMP, and NF-κB, and promote osteoblast proliferation. Swertiamarin has antioxidant and hepatoprotective effects against carbon tetrachloride induced rat liver toxicity through the Nrf2/HO-1 pathway. Swertiamarin can attenuate inflammatory mediators by regulating JAK2/STAT3 transcription factors in adjuvant induced arthritis rats. Swertiamarin can be used in the research of diabetes and arthritis.

MSU38225 is a selective Nrf2 inhibitor. MSU38225 increases ROS levels by inhibiting antioxidant production. MSU38225 arrests cells at the G₂/M phase, enhances cellular sensitivity to chemotherapeutic agents, and exerts synergistic effects with Carboplatin (HY-17393) and 5-fluorouracil (HY-90006). MSU38225 exhibits anticancer activity against lung cancer. MSU38225 can be used in research related to non-small cell lung cancer.

Monotropein is an iridoid glycoside that can be isolated from the roots of Morinda officinalis. Monotropein inhibits the expression of inflammatory mediators in dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein exerts protective effects against IL-1β-induced apoptosis and catabolic responses on osteoarthritis chondrocytes. Monotropein has cartilage protective activity. Monotropein can alleviate Cisplatin (HY-17394)-induced acute kidney injury by inhibiting oxidative damage, inflammation and apoptosis through activation of Nrf2/HO-1 pathway and inhibition of NF-κB signaling. Monotropein can be studied in research for osteoarthritis, acute kidney injury and acute lung injury.

Epmedin C (Epimedin-C; Baohuoside-VI) is an orally active anti-inflammatory agent and immunomodulator that binds to multiple key proteins including UCP1, Caspase-1, CDK2 and Keap1. Epmedin C inhibits epithelial cell proliferation by disrupting the complex function of CDK2/Cyclin E. Epmedin C also upregulates Nrf2 expression, reduces ROS levels and inhibits pro-inflammatory cytokine secretion, thereby effectively restoring antibody production and alleviating tissue damage. Epmedin C has good safety with no hepatotoxicity or skin sensitization, and it has been used in studies on diseases such as obesity, Deoxynivalenol (HY-N6684)-induced immunotoxicity and mammary hyperplasia.

Chebulic acid is a phenolic acid compound isolated from Terminalia chebula with strong antioxidant activity, which breaks protein cross-links induced by advanced glycation end products (AGEs) and inhibits the formation of AGEs. Chebulic acid is effective in controlling elevated metabolic parameters, oxidative stress, and liver damage, supporting its beneficial role in asthma, diabetes, and liver protection.

Angelic acid is a ferroptosis inducer, targeting NRF2 degradation. Angelic acid binds to NRF2 protein and promotes NRF2 degradation via ubiquitination-proteasome pathway, relieves the inhibitory effect of NRF2 on oxidative stress and lipid peroxidation. Then, Angelic acid induces ferroptosis in tumor cells. Angelic acid can enhance the accumulation of intracellular reactive oxygen species (ROS), upregulate ferroptosis-related markers CHAC1 and PTGS2, and synergize with ferroptosis inducers to enhance anti-tumor effects. Angelic acid also has the activity of scavenging UVA-induced ROS in vitro, inhibiting skin fibroblast senescence and extracellular matrix degradation. Angelic Acid helps wound healing with sedative activity.

Moracin N is a benzofuran compound. At low concentrations, Moracin N activates the Keap1/Nrf2 pathway, downregulates the expression of FTH1 and ACSL4, enhances glutathione synthesis, and inhibits neuronal ferroptosis. At high concentrations, Moracin N induces ROS accumulation, activates mitochondrial apoptosis, and triggers autophagy-mediated cell death by inhibiting the AKT/mTOR pathway. Moracin N can be used in research related to non-small cell lung cancer, hepatocellular carcinoma and ischemic brain injury.

RA839 is a selective Nrf2/ARE pathway agonist and non-covalent small molecule binder of Keap1 (K_d is approximately 6 μM). RA839 prevents inducible nitric oxide synthase expression and nitric oxide release. RA839 exerts anti-rotaviral and anti-inflammatory effects.

Gomisin N is an orally active lignan compound. Gomisin N can be isolated from Schisandra chinensis. Gomisin N induces Apoptosis in a variety of cells. Gomisin N activates AMPK, Akt, MAPK/ERK, Nrf2, caspase-3 and PARP-1. Gomisin N inhibits GSK3β, nitric oxide (NO), and proinflammatory cytokines (IL-1β, IL-6, TNF-α). Gomisin N has anti-inflammatory, antioxidant, anti-obesity, anti-diabetic, and anti-melanogenesis activities. Gomisin N has anti-tumor activity against cervical cancer and liver cancer. Gomisin N improves Alzheimer's disease.

DI-1859 is a DCN1 and cullin 3 inhibitor with a K_i of <1 nM against human DCN1. DI-1859 forms a covalent bond with Cys115 of DCN1, cleaves its dimethylamino group, disrupts the DCN1-UBC12 interaction, and selectively inhibits the neddylation modification of cullin 3 relative to other cullins. DI-1859 inactivates CRL3, promotes the accumulation of NRF2 and SLC7A11, upregulates the expression of HO-1 and NQO1, reduces reactive oxygen species (ROS) levels, enhances insulin signaling, promotes insulin secretion, activates RhoA, regulates the phosphorylation of AKT, without completely blocking the neddylation modification of cullin 3 or restoring the expression of IRS-1. DI-1859 can be used in the research of Acetaminophen (HY-66005)-induced hepatotoxicity, hyperglycemia, metabolic dysfunction-associated steatotic liver disease, insulin resistance, breast cancer and lung cancer.

Ezetimibe ketone is an orall active Nrf2 activator and ROS inhibitor. Ezetimibe ketone attenuates H₂O₂-induced reactive oxygen species production and reduces H₂O₂-induced apoptosis in renal tubular epithelial cells. Ezetimibe ketone suppresses renal tubular injury and inflammation.

Rosolutamide (ASC-JM17) is an orally active Nrf1/Nrf2 activator. Rosolutamide activates Hsf1 pathways, upregulates proteasome subunits and antioxidant enzymes, induces proteasome complex structural rearrangement, and enhances ubiquitin-proteasome system-mediated degradation. Rosolutamide reduces mutant androgen receptor and ataxin-3 aggregates, restores mitochondrial function, attenuates reactive oxygen species (ROS) levels, induces apoptosis and ferroptosis, and inhibits cancer cell growth. Rosolutamide can be used for the research of spinal and bulbar muscular atrophy, Huntington’s disease, and temozolomide-resistant glioblastoma.

Clemastine (HS-592; Meclastine) is an orally active, blood-brain barrier-permeable H1 histamine receptor (H1 histamine receptor) antagonist with potent antiallergic effects. Clemastine also antagonizes muscarinic acetylcholine receptors (mAChR), particularly the M1 and M4 subtypes. In addition to antihistamine effects, Clemastine exhibits multiple pharmacological activities, especially in promoting central nervous system remyelination, activating autophagy and pyroptosis, exerting anti-apoptotic and neuroprotective effects, and suppressing inflammation.

Glycycoumarin is a potent antispasmodic agent. Glycycoumarin is a major bioactive coumarin of licorice and exhibits antispasmodic activity. Glycycoumarin also has hepatoprotective effect. Glycycoumarin can be used for the research of abdominal pain and liver diseases.

Mesaconic acid (Citronic acid; Methylfumaric acid) is an orally active anti-inflammatory and antioxidant agent. Mesaconic acid reduces the level of NF-κB in colon tissues, downregulates the expression of Keap1 and Bax, upregulates the expression of Nrf2 and Bcl2, and decreases the expression of Caspase-1. Mesaconic acid reduces the levels of NLRP3, ASC and Casp-1 in colon, liver and kidney tissues. Mesaconic acid reduces pro-inflammatory cytokine levels, increases the level of the anti-inflammatory cytokine IL-10, elevates NAD⁺ levels, regulates oxidative stress markers and antioxidant enzyme levels, and upregulates intestinal barrier proteins in colon, liver and kidney tissues. Mesaconic acid increases the abundance of beneficial gut bacteria and reduces the abundance of harmful gut bacteria in rapidly aging mice, and exhibits anti-aging properties. Mesaconic acid acts as a flame retardant and serves as a competitive inhibitor of fumarate reduction. Mesaconic acid can be used in the research of aging-related inflammation.

Flumethasone (Flumetasone) is an orally active, high selective and potent glucocorticoid receptor (GR) agonist. Flumethasone activates GR to inhibit nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokine production (TNF-α, IL-1β) and promotes anti-inflammatory gene expression (IL-10), while also regulating metabolic enzyme activity (tyrosine aminotransferase induction). Flumethasone is promising for research of inflammatory diseases, cancer, and endocrine regulation.