{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:07:09Z","timestamp":1784264829172,"version":"3.55.0"},"reference-count":120,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fifth Batch of the National Training Program for Outstanding Clinical Talents in Traditional Chinese Medicine","award":["National Traditional Chinese Medicine Personnel Education Letter [2022] No. 239"],"award-info":[{"award-number":["National Traditional Chinese Medicine Personnel Education Letter [2022] No. 239"]}]},{"DOI":"10.13039\/100007847","name":"Natural Science Foundation of Jilin Province","doi-asserted-by":"crossref","award":["YDZJ202401133ZYTS"],"award-info":[{"award-number":["YDZJ202401133ZYTS"]}],"id":[{"id":"10.13039\/100007847","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which secondary brain injury is driven by oxidative stress, iron overload, ferroptosis, neuroinflammation, blood\u2013brain barrier disruption, and defective hematoma clearance. Nrf2 is a redox-sensitive transcription factor that coordinates antioxidant defense, iron handling, inflammatory regulation, and neurovascular unit protection through downstream effectors such as HO-1, NQO1, GPX4, and SLC7A11. Plant-derived natural compounds have been widely investigated in experimental ICH models; however, increased Nrf2 expression or nuclear translocation alone does not establish Nrf2-dependent neuroprotection. Here, we critically appraise preclinical evidence linking plant-derived natural compounds to Nrf2-centered signaling in ICH and classify the evidence into three levels: causal Nrf2-dependent evidence, Nrf2-associated evidence, and indirect or context-transferred evidence. Representative flavonoids, phenolics, terpenoids, lignans, steroidal lactones, and other bioactive compounds are evaluated with attention to ICH-model relevance, causal pathway validation, pharmacokinetic limitations, brain exposure, and therapeutic window. Current evidence indicates that only a limited subset of compounds has been validated by genetic or pharmacological Nrf2 inhibition, whereas most remain supported by pathway association rather than causality, and preclinical studies rely predominantly on young healthy rodent models with early post-ICH intervention. Notably, no compound currently reaches relatively high translational priority because perihematomal brain exposure, delayed-treatment efficacy, and long-term safety evidence remain largely unavailable. We therefore propose an evidence-based prioritization framework integrating Nrf2 causality, ICH-specific efficacy, brain bioavailability, and translational readiness. This review clarifies the mechanistic boundaries of Nrf2-targeted natural compounds and outlines priorities for rigorous translational research in ICH.<\/jats:p>","DOI":"10.3390\/antiox15070878","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plant-Derived Natural Compounds and Nrf2-Centered Redox Signaling in Intracerebral Hemorrhage: Evidence Grading, Mechanistic Boundaries, and Translational Challenges"],"prefix":"10.3390","volume":"15","author":[{"given":"Xu","family":"Gao","sequence":"first","affiliation":[{"name":"Basic Medical College, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhao","family":"Chang","sequence":"additional","affiliation":[{"name":"Basic Medical College, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxin","family":"Liu","sequence":"additional","affiliation":[{"name":"Basic Medical College, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7270-5593","authenticated-orcid":false,"given":"Tong","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Nursing College, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Nursing College, Changchun University of Traditional Chinese Medicine, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/s41582-024-01035-w","article-title":"Intracerebral Haemorrhage-Mechanisms, Diagnosis and Prospects for Treatment and Prevention","volume":"20","author":"Seiffge","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e282","DOI":"10.1161\/STR.0000000000000407","article-title":"2022 Guideline for the Management of Patients with Spontaneous Intracerebral Hemorrhage: A Guideline from the American Heart Association\/American Stroke Association","volume":"53","author":"Greenberg","year":"2022","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1136\/jnnp-2021-327098","article-title":"Secondary Injury and Inflammation after Intracerebral Haemorrhage: A Systematic Review and Meta-Analysis of Molecular Markers in Patient Brain Tissue","volume":"93","author":"Loan","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Shao, L., Chen, S., and Ma, L. (2022). Secondary Brain Injury by Oxidative Stress after Cerebral Hemorrhage: Recent Advances. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.853589"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/s40001-025-03809-4","article-title":"Ferroptosis Associated with Secondary Brain Damage Induced by Hypertensive Underlying Biological Processes in Intracerebral Hemorrhage and Therapeutic Prospects","volume":"31","author":"Luo","year":"2026","journal-title":"Eur. J. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic Targeting of the NRF2 and KEAP1 Partnership in Chronic Diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/jnc.12974","article-title":"Cleaning up after ICH: The Role of Nrf2 in Modulating Microglia Function and Hematoma Clearance","volume":"133","author":"Zhao","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Yu, W., Liu, Y., Chang, W., Wang, M., and Zhang, L. (2022). Regulation of Nuclear Factor Erythroid-2-Related Factor 2 as a Potential Therapeutic Target in Intracerebral Hemorrhage. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.995518"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Duan, L., Zhang, Y., Yang, Y., Su, S., Zhou, L., Lo, P.-C., Cai, J., Qiao, Y., Li, M., and Huang, S. (2021). Baicalin Inhibits Ferroptosis in Intracerebral Hemorrhage. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.629379"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.freeradbiomed.2024.09.035","article-title":"Naturally-Derived Modulators of the Nrf2 Pathway and Their Roles in the Intervention of Diseases","volume":"225","author":"Wang","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s11064-025-04544-2","article-title":"Kaempferol Plays a Neuroprotection Role by Alleviating Oxidative Stress via AKT\/Nrf2\/HO-1 Pathway and Inhibiting Apoptosis in Intracerebral Hemorrhage","volume":"50","author":"Huo","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1007\/s10571-023-01325-9","article-title":"Macrophage\/Microglia Sirt3 Contributes to the Anti-Inflammatory Effects of Resveratrol against Experimental Intracerebral Hemorrhage in Mice","volume":"43","author":"Sun","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1128\/MCB.15.8.4184","article-title":"Cloning and Characterization of a Novel Erythroid Cell-Derived CNC Family Transcription Factor Heterodimerizing with the Small Maf Family Proteins","volume":"15","author":"Itoh","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ngo, V., and Duennwald, M.L. (2022). Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11122345"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1177\/0271678X20984565","article-title":"Potential Therapeutic Effects of Nrf2 Activators on Intracranial Hemorrhage","volume":"41","author":"Imai","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.abb.2016.08.005","article-title":"Keap1, the Cysteine-Based Mammalian Intracellular Sensor for Electrophiles and Oxidants","volume":"617","author":"Kostov","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e000238","DOI":"10.1136\/bmjno-2021-000238","article-title":"Nrf2 Activation in the Human Brain after Stroke Due to Supratentorial Intracerebral Haemorrhage: A Case\u2013Control Study","volume":"4","author":"Christopher","year":"2022","journal-title":"BMJ Neurol. Open"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3215391","DOI":"10.1155\/2016\/3215391","article-title":"Oxidative Stress in Intracerebral Hemorrhage: Sources, Mechanisms, and Therapeutic Targets","volume":"2016","author":"Hu","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Duan, C., Jiao, D., Wang, H., Wu, Q., Men, W., Yan, H., and Li, C. (2022). Activation of the PPAR\u03b3 Prevents Ferroptosis-Induced Neuronal Loss in Response to Intracerebral Hemorrhage through Synergistic Actions with the Nrf2. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.869300"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4564471","DOI":"10.1155\/2022\/4564471","article-title":"The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice","volume":"2022","author":"Hu","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Saha, S., Buttari, B., Panieri, E., Profumo, E., and Saso, L. (2020). An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules, 25.","DOI":"10.3390\/molecules25225474"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 Signaling Pathway: Pivotal Roles in Inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA) -Mol. Basis Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hennig, P., Garstkiewicz, M., Grossi, S., Di Filippo, M., French, L.E., and Beer, H.-D. (2018). The Crosstalk between Nrf2 and Inflammasomes. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020562"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hennig, P., Fenini, G., Di Filippo, M., Karakaya, T., and Beer, H.-D. (2021). The Pathways Underlying the Multiple Roles of P62 in Inflammation and Cancer. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070707"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115552","DOI":"10.1016\/j.expneurol.2025.115552","article-title":"Nrf2-SRA Pathway Promotes Hematoma Clearance after Intracerebral Hemorrhage: Mechanistic Insights and Clinical Implications","volume":"396","author":"Sang","year":"2026","journal-title":"Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70706","DOI":"10.1002\/cns.70706","article-title":"Apelin-13 Attenuates Blood\u2013Brain Barrier Dysfunction Following Intracerebral Hemorrhage via Targeting the Keap1\/Nrf2 Signaling","volume":"31","author":"Guo","year":"2025","journal-title":"CNS Neurosci. Ther."},{"key":"ref_28","first-page":"2226","article-title":"Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage","volume":"23","author":"Regan","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1161\/STROKEAHA.115.008686","article-title":"Astrocyte Overexpression of Heme Oxygenase-1 Improves Outcome after Intracerebral Hemorrhage","volume":"46","author":"Song","year":"2015","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1093\/brain\/awm095","article-title":"Heme Oxygenase-1 Exacerbates Early Brain Injury after Intracerebral Haemorrhage","volume":"130","author":"Wang","year":"2007","journal-title":"Brain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1111\/j.1471-4159.2007.04885.x","article-title":"Time Course of Increased Heme Oxygenase Activity and Expression after Experimental Intracerebral Hemorrhage: Correlation with Oxidative Injury","volume":"103","author":"Chen","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1177\/0271678X16655814","article-title":"Distinct Role of Heme Oxygenase-1 in Early- and Late-Stage Intracerebral Hemorrhage in 12-Month-Old Mice","volume":"37","author":"Zhang","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41572-023-00428-3","article-title":"Intracerebral Haemorrhage","volume":"9","author":"Puy","year":"2023","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1161\/STROKEAHA.107.486506","article-title":"Transcription Factor Nrf2 Protects the Brain from Damage Produced by Intracerebral Hemorrhage","volume":"38","author":"Zhao","year":"2007","journal-title":"Stroke"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.brainres.2018.08.021","article-title":"A Novel Nrf2 Activator, RS9, Attenuates Secondary Brain Injury after Intracerebral Hemorrhage in Sub-Acute Phase","volume":"1701","author":"Sugiyama","year":"2018","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1164\/rccm.201705-0903OC","article-title":"Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists","volume":"198","author":"Bewley","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.freeradbiomed.2020.03.012","article-title":"A Triterpenoid Nrf2 Activator, RS9, Promotes LC3-Associated Phagocytosis of Photoreceptor Outer Segments in a P62-Independent Manner","volume":"152","author":"Saito","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1038\/s41598-024-53836-0","article-title":"NRF2 Activation Ameliorates Blood\u2013Brain Barrier Injury after Cerebral Ischemic Stroke by Regulating Ferroptosis and Inflammation","volume":"14","author":"Fan","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Loan, J.J.M., Al-Shahi Salman, R., McColl, B.W., and Hardingham, G.E. (2022). Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage. Biomolecules, 12.","DOI":"10.3390\/biom12101438"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.freeradbiomed.2007.04.020","article-title":"Role of Nrf2 in Protection against Intracerebral Hemorrhage Injury in Mice","volume":"43","author":"Wang","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, M., Zhang, Y., Wu, Q., Ma, S., Wang, C., and Sang, J. (2025). Medicine-Food Homology Bioactives in Parkinson\u2019s Disease: Multi-Target Oxidative-Stress Modulation and Translation to Dietary Supplements. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1677749"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1080\/13880209.2018.1492620","article-title":"A Comprehensive Review on Phytochemistry, Pharmacology, and Flavonoid Biosynthesis of Scutellaria Baicalensis","volume":"56","author":"Wang","year":"2018","journal-title":"Pharm. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ctrv.2008.09.005","article-title":"New Therapeutic Aspects of Flavones: The Anticancer Properties of Scutellaria and Its Main Active Constituents Wogonin, Baicalein and Baicalin","volume":"35","year":"2009","journal-title":"Cancer Treat. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3109\/00498251003663724","article-title":"Baicalin, an Emerging Multi-Therapeutic Agent: Pharmacodynamics, Pharmacokinetics, and Considerations from Drug Development Perspectives","volume":"40","author":"Srinivas","year":"2010","journal-title":"Xenobiotica Fate Foreign Compd. Biol. Syst."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e70174","DOI":"10.1002\/ddr.70174","article-title":"Baicalin Promotes Recovery Following Intracerebral Hemorrhage by Inhibiting Ferroptosis in Brain Tissue through Modulation of AKT\/Nrf2\/GPX4 Axis","volume":"86","author":"Yu","year":"2025","journal-title":"Drug Dev. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1080\/00207454.2022.2080676","article-title":"Baicalein Ameliorates Oxidative Stress and Brain Injury after Intracerebral Hemorrhage by Activating the Nrf2\/ARE Pathway via miR-106a-5p\/PHLPP2 Axis","volume":"133","author":"Tang","year":"2023","journal-title":"Int. J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3892\/etm.2024.12639","article-title":"Protective Effects of Flavonoids against Intracerebral and Subarachnoid Hemorrhage (Review)","volume":"28","author":"Dong","year":"2024","journal-title":"Exp. Ther. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/s10753-021-01569-x","article-title":"Mechanism of Baicalein in Brain Injury after Intracerebral Hemorrhage by Inhibiting the ROS\/NLRP3 Inflammasome Pathway","volume":"45","author":"Chen","year":"2022","journal-title":"Inflammation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jep.2018.05.019","article-title":"Anti-Inflammatory Effects of Luteolin: A Review of in Vitro, in Vivo, and in Silico Studies","volume":"225","author":"Aziz","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e41068","DOI":"10.1016\/j.heliyon.2024.e41068","article-title":"Extraction, Detection, Bioactivity, and Product Development of Luteolin: A Review","volume":"10","author":"Ren","year":"2024","journal-title":"Heliyon"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Tan, X., Yang, Y., Xu, J., Zhang, P., Deng, R., Mao, Y., He, J., Chen, Y., Zhang, Y., and Ding, J. (2019). Luteolin Exerts Neuroprotection via Modulation of the P62\/Keap1\/Nrf2 Pathway in Intracerebral Hemorrhage. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01551"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"101059","DOI":"10.1016\/j.redox.2018.11.017","article-title":"NRF2 and NF-\u03baB Interplay in Cerebrovascular and Neurodegenerative Disorders: Molecular Mechanisms and Possible Therapeutic Approaches","volume":"21","author":"Sivandzade","year":"2019","journal-title":"Redox Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"110044","DOI":"10.1016\/j.biopha.2020.110044","article-title":"Luteolin Alleviates Neuroinflammation via Downregulating the TLR4\/TRAF6\/NF-\u03baB Pathway after Intracerebral Hemorrhage","volume":"126","author":"Yang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jep.2017.08.035","article-title":"Molecular Understanding of Epigallocatechin Gallate (EGCG) in Cardiovascular and Metabolic Diseases","volume":"210","author":"Eng","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1016\/j.bcp.2011.07.093","article-title":"Green Tea Catechin, Epigallocatechin-3-Gallate (EGCG): Mechanisms, Perspectives and Clinical Applications","volume":"82","author":"Singh","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"111812","DOI":"10.1016\/j.brainresbull.2026.111812","article-title":"Epigallocatechin Gallate Ameliorates Brain Injuries after Intracerebral Hemorrhage by Inhibiting Ferroptosis through Upregulation of Nrf2-Keap1 Pathway","volume":"237","author":"Zhou","year":"2026","journal-title":"Brain Res. Bull."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"31474","DOI":"10.1038\/s41598-024-82938-y","article-title":"EGCG Activates Keap1\/P62\/Nrf2 Pathway, Inhibits Iron Deposition and Apoptosis in Rats with Cerebral Hemorrhage","volume":"14","author":"Hao","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"105603","DOI":"10.1016\/j.neuint.2023.105603","article-title":"The Protective Effects of EGCG Was Associated with HO-1 Active and Microglia Pyroptosis Inhibition in Experimental Intracerebral Hemorrhage","volume":"170","author":"Bao","year":"2023","journal-title":"Neurochem. Int."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Farhan, M. (2022). Green Tea Catechins: Nature\u2019s Way of Preventing and Treating Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810713"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/0929867327666191230104958","article-title":"Dietary Epicatechin, a Novel Anti-Aging Bioactive Small Molecule","volume":"28","author":"Si","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7898","DOI":"10.1007\/s12035-016-0271-y","article-title":"(-)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways","volume":"54","author":"Lan","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"120827","DOI":"10.1016\/j.jep.2025.120827","article-title":"A Comprehensive Review of Glycyrrhiza Glabra in the Management of Rheumatoid Arthritis: Ethnopharmacology, Pharmacological Mechanisms and Synergistic Therapeutic Strategies","volume":"356","author":"Prajapati","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"117059","DOI":"10.1016\/j.jep.2023.117059","article-title":"Isoliquiritigenin, a Potential Therapeutic Agent for Treatment of Inflammation-Associated Diseases","volume":"318","author":"Chen","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12974-017-0895-5","article-title":"Isoliquiritigenin Alleviates Early Brain Injury after Experimental Intracerebral Hemorrhage via Suppressing ROS- and\/or NF-\u03baB-Mediated NLRP3 Inflammasome Activation by Promoting Nrf2 Antioxidant Pathway","volume":"14","author":"Zeng","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Periferakis, A., Periferakis, K., Badarau, I.A., Petran, E.M., Popa, D.C., Caruntu, A., Costache, R.S., Scheau, C., Caruntu, C., and Costache, D.O. (2022). Kaempferol: Antimicrobial Properties, Sources, Clinical, and Traditional Applications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315054"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1080\/14787210.2021.1863145","article-title":"Calycosin: A Review of Its Pharmacological Effects and Application Prospects","volume":"19","author":"Deng","year":"2021","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"100881","DOI":"10.1016\/j.hermed.2024.100881","article-title":"Astragalus Mongholicus: A Review of Its Pharmacological Mechanisms against Gastric Cancer","volume":"45","author":"Tibenda","year":"2024","journal-title":"J. Herb. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"9952578","DOI":"10.1155\/2021\/9952578","article-title":"Pharmaceutical Values of Calycosin: One Type of Flavonoid Isolated from Astragalus","volume":"2021","author":"Gong","year":"2021","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"583","DOI":"10.4155\/fmc-2019-0311","article-title":"Neuroprotective Functions of Calycosin against Intracerebral Hemorrhage-Induced Oxidative Stress and Neuroinflammation","volume":"12","author":"Chen","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107127","DOI":"10.1016\/j.jff.2025.107127","article-title":"Resveratrol in Food Systems: Challenges, Innovations, and Health Potential","volume":"136","author":"Bouchard","year":"2026","journal-title":"J. Funct. Foods"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Kogut, \u0141., Puchalski, C., Katry\u0144ska, D., and Zagu\u0142a, G. (2026). The Multidirectional Biological Activity of Resveratrol: Molecular Mechanisms, Systemic Effects and Therapeutic Potential\u2014A Review. Nutrients, 18.","DOI":"10.3390\/nu18020313"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Bonsack, F., Alleyne, C.H., and Sukumari-Ramesh, S. (2017). Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00228"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Liu, J., Liao, H., Chen, Y., Zhu, H., Li, X., Liu, J., Xiang, Q., Zeng, F., and Yang, Q. (2022). Resveratrol Inhibits Oxidative Stress and Regulates M1\/M2-Type Polarization of Microglia via Mediation of the Nrf2\/Shh Signaling Cascade after OGD\/R Injury in Vitro. J. Pers. Med., 12.","DOI":"10.3390\/jpm12122087"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Farina, M., Vieira, L.E., Buttari, B., Profumo, E., and Saso, L. (2021). The Nrf2 Pathway in Ischemic Stroke: A Review. Molecules, 26.","DOI":"10.3390\/molecules26165001"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1007\/s12272-023-01463-0","article-title":"Review on Pharmacological Effects of Gastrodin","volume":"46","author":"Xiao","year":"2023","journal-title":"Arch. Pharmacal Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1007\/s00210-023-02920-9","article-title":"Gastrodin: A Comprehensive Pharmacological Review","volume":"397","author":"Wang","year":"2024","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"104483","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.104483","article-title":"Gastrodin Attenuates Neuronal Apoptosis and Neurological Deficits after Experimental Intracerebral Hemorrhage","volume":"29","author":"Liu","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis. Off. J. Natl. Stroke Assoc."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Hewlings, S.J., and Kalman, D.S. (2017). Curcumin: A Review of Its Effects on Human Health. Foods, 6.","DOI":"10.3390\/foods6100092"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wei, Y., Li, H., Li, Y., Zeng, Y., Quan, T., Leng, Y., Chang, E., Bai, Y., Bian, Y., and Hou, Y. (2024). Advances of Curcumin in Nervous System Diseases: The Effect of Regulating Oxidative Stress and Clinical Studies. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1496661"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Duan, C., Wang, H., Jiao, D., Geng, Y., Wu, Q., Yan, H., and Li, C. (2022). Curcumin Restrains Oxidative Stress of after Intracerebral Hemorrhage in Rat by Activating the Nrf2\/HO-1 Pathway. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.889226"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e2311128","DOI":"10.1002\/smll.202311128","article-title":"Platelet Membrane-Coated Curcumin-PLGA Nanoparticles Promote Astrocyte-Neuron Transdifferentiation for Intracerebral Hemorrhage Treatment","volume":"20","author":"Xu","year":"2024","journal-title":"Small"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"952943","DOI":"10.1155\/2014\/952943","article-title":"A Review on Protocatechuic Acid and Its Pharmacological Potential","volume":"2014","author":"Kakkar","year":"2014","journal-title":"ISRN Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Liang, S., Zhao, Z., Liu, L., Zhang, Y., and Liu, X. (2024). Research Progress on the Mechanisms of Protocatechuic Acid in the Treatment of Cognitive Impairment. Molecules, 29.","DOI":"10.3390\/molecules29194724"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1097\/WNR.0000000000001542","article-title":"Protocatechuic Acid Attenuates Brain Edema and Blood-Brain Barrier Disruption after Intracerebral Hemorrhage in Mice by Promoting Nrf2\/HO-1 Pathway","volume":"31","author":"Xi","year":"2020","journal-title":"Neuroreport"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Surien, O., Masre, S.F., Basri, D.F., and Ghazali, A.R. (2023). Potential Chemopreventive Role of Pterostilbene in Its Modulation of the Apoptosis Pathway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119707"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Liu, P., Tang, W., Xiang, K., and Li, G. (2023). Pterostilbene in the Treatment of Inflammatory and Oncological Diseases. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1323377"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"107950","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.107950","article-title":"Pterostilbene Ameliorates Oxidative Stress and Neuronal Apoptosis after Intracerebral Hemorrhage via the Sirtuin 1-Mediated Nrf2 Pathway in Vivo and in Vitro","volume":"33","author":"Cui","year":"2024","journal-title":"J. Stroke Cerebrovasc. Dis. Off. J. Natl. Stroke Assoc."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Wu, Y., Hu, Q., Wang, X., Cheng, H., Yu, J., Li, Y., Luo, J., Zhang, Q., Wu, J., and Zhang, G. (2023). Pterostilbene Attenuates Microglial Inflammation and Brain Injury after Intracerebral Hemorrhage in an OPA1-Dependent Manner. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1172334"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"12427","DOI":"10.1038\/s41598-024-63277-4","article-title":"Salvianolic Acid a Inhibits Ferroptosis and Protects against Intracerebral Hemorrhage","volume":"14","author":"Shi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_91","first-page":"21","article-title":"Research Progress of Small-Molecule Natural Medicines for the Treatment of Ischemic Stroke","volume":"23","author":"Liu","year":"2025","journal-title":"Chin. J. Nat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Shang, Y.-F., Feng, W.-D., Liu, D.-N., Zhang, W.-F., Xu, S., Feng, D.-H., Du, G.-H., and Wang, Y.-H. (2025). Salvianolic Acid a Activates Nrf2-Related Signaling Pathways to Inhibit Ferroptosis to Improve Ischemic Stroke. Molecules, 30.","DOI":"10.3390\/molecules30153266"},{"key":"ref_93","first-page":"208349","article-title":"A Review of the Pharmacological Effects of the Dried Root of Polygonum Cuspidatum (Hu Zhang) and Its Constituents. Evid.-Based Complement","volume":"2013","author":"Zhang","year":"2013","journal-title":"Altern. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1007\/s12031-020-01546-3","article-title":"Effect of Polydatin on Neurological Function and the Nrf2 Pathway during Intracerebral Hemorrhage","volume":"70","author":"Zhao","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"113710","DOI":"10.1016\/j.ejmech.2021.113710","article-title":"Andrographolide and Its Derivatives: Current Achievements and Future Perspectives","volume":"224","author":"Zhang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/ptr.7324","article-title":"Andrographolide: A Review of Its Pharmacology, Pharmacokinetics, Toxicity and Clinical Trials and Pharmaceutical Researches","volume":"36","author":"Zeng","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_97","first-page":"92","article-title":"The protective effect of andrographolide on the blood\u2013cerebrospinal fluid barrier in rats with intracerebral hemorrhage through the Nrf2\/HO-1 pathway","volume":"52","author":"Jiang","year":"2023","journal-title":"J. Med. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"113297","DOI":"10.1016\/j.biopha.2022.113297","article-title":"An Evaluation on Potential Anti-Oxidant and Anti-Inflammatory Effects of Crocin","volume":"153","author":"Bastani","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7395","DOI":"10.1007\/s00210-024-03131-6","article-title":"Potential Therapeutic Effects of Crocin","volume":"397","author":"Pourmousavi","year":"2024","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"156097","DOI":"10.1016\/j.phymed.2024.156097","article-title":"Saffron and Its Major Constituents against Neurodegenerative Diseases: A Mechanistic Review","volume":"135","author":"Abdian","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1007\/s12640-022-00500-y","article-title":"Crocin Alleviates Intracerebral Hemorrhage\u2013Induced Neuronal Ferroptosis by Facilitating Nrf2 Nuclear Translocation","volume":"40","author":"Wang","year":"2022","journal-title":"Neurotoxic. Res."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Zhou, C., Lu, M., Cheng, J., Rohani, E.R., Hamezah, H.S., Han, R., and Tong, X. (2022). Review on the Pharmacological Properties of Phillyrin. Molecules, 27.","DOI":"10.3390\/molecules27123670"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"117275","DOI":"10.1016\/j.jep.2023.117275","article-title":"Review of the Therapeutic Potential of Forsythiae Fructus on the Central Nervous System: Active Ingredients and Mechanisms of Action","volume":"319","author":"Zhang","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"174439","DOI":"10.1016\/j.ejphar.2021.174439","article-title":"The Neuroprotective Effect of Phillyrin in Intracerebral Hemorrhagic Mice Is Produced by Activation of the Nrf2 Signaling Pathway","volume":"909","author":"Guo","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.3390\/molecules14072373","article-title":"Steroidal Lactones from Withania Somnifera, an Ancient Plant for Novel Medicine","volume":"14","author":"Mirjalili","year":"2009","journal-title":"Molecules"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/1566524023666230418094708","article-title":"The Therapeutic Effects of Withaferin a against Cancer: Overviewand Updates","volume":"24","author":"Abeesh","year":"2024","journal-title":"Curr. Mol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.4103\/1673-5374.355822","article-title":"Withaferin a Inhibits Ferroptosis and Protects against Intracerebral Hemorrhage","volume":"18","author":"Zhou","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"20605","DOI":"10.1039\/D5RA00755K","article-title":"Therapeutic Potential of Betaine and Its Derivatives in Cancer Treatment: A Comprehensive Review","volume":"15","author":"Hassan","year":"2025","journal-title":"RSC Adv."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5133","DOI":"10.1007\/s00216-017-0461-0","article-title":"New Approaches for Extraction and Determination of Betaine from Beta Vulgaris Samples by Hydrophilic Interaction Liquid Chromatography-Tandem Mass Spectrometry","volume":"409","author":"Rivoira","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"102634","DOI":"10.1016\/j.arr.2024.102634","article-title":"Betaine and Aging: A Narrative Review of Findings, Possible Mechanisms, Research Perspectives, and Practical Recommendations","volume":"104","author":"Zawieja","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Chen, J., Lu, X., Liu, S., Hu, W., Zhou, X., and Wang, Z. (2026). Betaine Inhibits Ferroptosis after Intracerebral Hemorrhage by Activating the Nrf2\/HO-1 Pathway. Antioxidants, 15.","DOI":"10.3390\/antiox15010135"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Delmas, D. (2020). Silymarin and Derivatives: From Biosynthesis to Health Benefits. Molecules, 25.","DOI":"10.3390\/molecules25102415"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"111109","DOI":"10.1016\/j.isci.2024.111109","article-title":"The Clinical Anti-Inflammatory Effects and Underlying Mechanisms of Silymarin","volume":"27","author":"Zhao","year":"2024","journal-title":"iScience"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Ranjan, S., and Gautam, A. (2023). Pharmaceutical Prospects of Silymarin for the Treatment of Neurological Patients: An Updated Insight. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1159806"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.biopha.2017.06.018","article-title":"Silymarin Prevents NLRP3 Inflammasome Activation and Protects against Intracerebral Hemorrhage","volume":"93","author":"Yuan","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"116797","DOI":"10.1016\/j.bcp.2025.116797","article-title":"Sulforaphane: An Emerging Star in Neuroprotection and Neurological Disease Prevention","volume":"233","author":"Wu","year":"2025","journal-title":"Biochem. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"103880","DOI":"10.1016\/j.ebiom.2022.103880","article-title":"Novel Targets, Treatments, and Advanced Models for Intracerebral Haemorrhage","volume":"76","author":"Zille","year":"2022","journal-title":"eBioMedicine"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1136\/svn-2020-000334","article-title":"Intracerebral Haemorrhage: From Clinical Settings to Animal Models","volume":"5","author":"Bai","year":"2020","journal-title":"Stroke Vasc. Neurol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1007\/s12975-020-00824-x","article-title":"Translational Intracerebral Hemorrhage Research: Has Current Neuroprotection Research ARRIVEd at a Standard for Experimental Design and Reporting?","volume":"11","author":"Liddle","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"103464","DOI":"10.1016\/j.redox.2024.103464","article-title":"Model Organisms for Investigating the Functional Involvement of NRF2 in Non-Communicable Diseases","volume":"79","author":"Rojo","year":"2025","journal-title":"Redox Biol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:35:54Z","timestamp":1784262954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":120,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["antiox15070878"],"URL":"https:\/\/doi.org\/10.3390\/antiox15070878","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]}}}