{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:44:05Z","timestamp":1790765045222,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["27080"],"award-info":[{"award-number":["27080"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Hyperforin (HPF) is an acylphloroglucinol compound found abundantly in Hypericum perforatum extract which exhibits antidepressant, anti-inflammatory, antimicrobial, and antitumor activities. Our recent study revealed a potent antimelanoma effect of HPF, which hinders melanoma cell proliferation, motility, colony formation, and induces apoptosis. Furthermore, we have identified glutathione peroxidase-4 (GPX-4), a key enzyme involved in cellular protection against iron-induced lipid peroxidation, as one of the molecular targets of HPF. Thus, in three BRAF-mutated melanoma cell lines, we investigated whether iron unbalance and lipid peroxidation may be a part of the molecular mechanisms underlying the antimelanoma activity of HPF. Initially, we focused on heme oxygenase-1 (HO-1), which catalyzes the heme group into CO, biliverdin, and free iron, and observed that HPF treatment triggered the expression of this inducible enzyme. In order to investigate the mechanism involved in HO-1 induction, we verified that HPF downregulates the BTB and CNC homology 1 (BACH-1) transcription factor, an inhibitor of the heme oxygenase 1 (HMOX-1) gene transcription. Remarkably, we observed a partial recovery of cell viability and an increase in the expression of the phosphorylated and active form of retinoblastoma protein when we suppressed the HMOX-1 gene using HMOX-1 siRNA while HPF was present. This suggests that the HO-1 pathway is involved in the cytostatic effect of HPF in melanoma cells. To explore whether lipid peroxidation is induced, we conducted cytofluorimetric analysis and observed a significant increase in the fluorescence of the BODIPY C-11 probe 48 h after HPF administration in all tested melanoma cell lines. To discover the mechanism by which HPF triggers lipid peroxidation, along with the induction of HO-1, we examined the expression of additional proteins associated with iron homeostasis and lipid peroxidation. After HPF administration, we confirmed the downregulation of GPX-4 and observed low expression levels of SLC7A11, a cystine transporter crucial for the glutathione production, and ferritin, able to sequester free iron. A decreased expression level of these proteins can sensitize cells to lipid peroxidation. On the other hand, HPF treatment resulted in increased expression levels of transferrin, which facilitates iron uptake, and LC3B proteins, a molecular marker of autophagy induction. Indeed, ferritin and GPX-4 have been reported to be digested during autophagy. Altogether, these findings suggest that HPF induced lipid peroxidation likely through iron overloading and decreasing the expression of proteins that protect cells from lipid peroxidation. Finally, we examined the expression levels of proteins associated with melanoma cell invasion and metastatic potential. We observed the decreased expression of CD133, octamer-4, tyrosine-kinase receptor AXL, urokinase plasminogen activator receptor, and metalloproteinase-2 following HPF treatment. These findings provide further support for our previous observations, demonstrating the inhibitory effects of HPF on cell motility and colony formation in soft agar, which are both metastasis-related processes in tumor cells.<\/jats:p>","DOI":"10.3390\/antiox12071369","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T16:08:32Z","timestamp":1688141312000},"page":"1369","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hyperforin Enhances Heme Oxygenase-1 Expression Triggering Lipid Peroxidation in BRAF-Mutated Melanoma Cells and Hampers the Expression of Pro-Metastatic Markers"],"prefix":"10.3390","volume":"12","author":[{"given":"Alessia","family":"Cardile","sequence":"first","affiliation":[{"name":"Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, School of Medicine, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Passarini","sequence":"additional","affiliation":[{"name":"Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, School of Medicine, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7336-3214","authenticated-orcid":false,"given":"Valentina","family":"Zanr\u00e8","sequence":"additional","affiliation":[{"name":"Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, School of Medicine, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2070-6046","authenticated-orcid":false,"given":"Alessandra","family":"Fiore","sequence":"additional","affiliation":[{"name":"Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, School of Medicine, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1310-9227","authenticated-orcid":false,"given":"Marta","family":"Menegazzi","sequence":"additional","affiliation":[{"name":"Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, School of Medicine, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115058","DOI":"10.1016\/j.bcp.2022.115058","article-title":"Carbon Monoxide (CO)\/Heme Oxygenase (HO)-1 in Gastrointestinal Tumors Pathophysiology and Pharmacology\u2014Possible Anti- and pro-Cancer Activities","volume":"201","author":"Krukowska","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nitti, M., Piras, S., Marinari, U.M., Moretta, L., Pronzato, M.A., and Furfaro, A.L. (2017). HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation. Antioxidants, 6.","DOI":"10.3390\/antiox6020029"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"166621","DOI":"10.1016\/j.bbadis.2022.166621","article-title":"Iron Cycle Disruption by Heme Oxygenase-1 Activation Leads to a Reduced Breast Cancer Cell Survival","volume":"1869","author":"Giorgi","year":"2023","journal-title":"Biochim. Biophys. Acta\u2014Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00432-022-04447-7","article-title":"The Dual Role and Mutual Dependence of Heme\/HO-1\/Bach1 Axis in the Carcinogenic and Anti-Carcinogenic Intersection","volume":"149","author":"Xu","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chiang, S.-K., Chen, S.-E., and Chang, L.-C. (2018). A Dual Role of Heme Oxygenase-1 in Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010039"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.jgg.2022.06.002","article-title":"Understanding the Mechanistic Regulation of Ferroptosis in Cancer: The Gene Matters","volume":"49","author":"Gao","year":"2022","journal-title":"J. Genet. Genom."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1089\/ars.2005.7.1688","article-title":"Molecular Basis of Heme Oxygenase-1 Induction: Implications for Chemoprevention and Chemoprotection","volume":"7","author":"Prawan","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101032","DOI":"10.1016\/j.jbc.2021.101032","article-title":"The Transcription Factor BACH1 at the Crossroads of Cancer Biology: From Epithelial-Mesenchymal Transition to Ferroptosis","volume":"297","author":"Igarashi","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106132","DOI":"10.1016\/j.intimp.2019.106132","article-title":"MicroRNA and Heme Oxygenase-1 in Allergic Disease","volume":"80","author":"Chen","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"789927","DOI":"10.3389\/fmolb.2021.789927","article-title":"MiR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1","volume":"8","author":"Tao","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12964-018-0313-3","article-title":"Heme Oxygenase 1 Facilitates Cell Proliferation via the B-Raf-ERK Signaling Pathway in Melanoma","volume":"17","author":"Liu","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Upadhyay, P.R., Starner, R.J., Swope, V.B., Wakamatsu, K., Ito, S., and Abdel-Malek, Z.A. (2022). Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility. Antioxidants, 11.","DOI":"10.3390\/antiox11061204"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s40257-017-0325-6","article-title":"Advanced Melanoma: Current Treatment Options, Biomarkers, and Future Perspectives","volume":"19","author":"Rozeman","year":"2018","journal-title":"Am. J. Clin. Derm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8796","DOI":"10.1038\/sj.onc.1208152","article-title":"Involvement of Overexpressed Wild-Type BRAF in the Growth of Malignant Melanoma Cell Lines","volume":"23","author":"Tanami","year":"2004","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1056\/NEJMoa1112302","article-title":"Survival in BRAF V600-Mutant Advanced Melanoma Treated with Vemurafenib","volume":"366","author":"Sosman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chiang, S.-K., Chen, S.-E., and Chang, L.-C. (2021). The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival. Cells, 10.","DOI":"10.3390\/cells10092401"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/ijc.32611","article-title":"HO-1 Downregulation Favors BRAFV600 Melanoma Cell Death Induced by Vemurafenib\/PLX4032 and Increases NK Recognition","volume":"146","author":"Furfaro","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Longhitano, L., Broggi, G., Giallongo, S., Failla, M., Puzzo, L., Avitabile, T., Tibullo, D., Distefano, A., Pittal\u00e0, V., and Reibaldi, M. (2022). Heme Oxygenase-1 Overexpression Promotes Uveal Melanoma Progression and Is Associated with Poor Clinical Outcomes. Antioxidants, 11.","DOI":"10.3390\/antiox11101997"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Was, H., Cichon, T., Smolarczyk, R., Lackowska, B., Mazur-Bialy, A., Mazur, M., Szade, A., Dominik, P., Mazan, M., and Kotlinowski, J. (2020). Effect of Heme Oxygenase-1 on Melanoma Development in Mice-Role of Tumor-Infiltrating Immune Cells. Antioxidants, 9.","DOI":"10.3390\/antiox9121223"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1089\/ars.2018.7554","article-title":"Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer","volume":"30","author":"Gandini","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hahn, D., Shin, S.H., and Bae, J.-S. (2020). Natural Antioxidant and Anti-Inflammatory Compounds in Foodstuff or Medicinal Herbs Inducing Heme Oxygenase-1 Expression. Antioxidants, 9.","DOI":"10.3390\/antiox9121191"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cbi.2012.06.006","article-title":"Phenylpropanoid Glycosides from Plant Cell Cultures Induce Heme Oxygenase 1 Gene Expression in a Human Keratinocyte Cell Line by Affecting the Balance of NRF2 and BACH1 Transcription Factors","volume":"199","author":"Sgarbossa","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Raineri, A., Campagnari, R., Dal Toso, R., Copetti, S., Gomez-Lira, M., and Menegazzi, M. (2021). 3,5-Dicaffeoylquinic Acid Lowers 3T3-L1 Mitotic Clonal Expansion and Adipocyte Differentiation by Enhancing Heme Oxygenase-1 Expression. Molecules, 26.","DOI":"10.3390\/molecules26165027"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.5009\/gnl210058","article-title":"Potential Role of Heme Oxygenase-1 in the Resolution of Experimentally Induced Colitis through Regulation of Macrophage Polarization","volume":"16","author":"Gwak","year":"2022","journal-title":"Gut Liver"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"153551","DOI":"10.1016\/j.phymed.2021.153551","article-title":"Shuganning Injection, a Traditional Chinese Patent Medicine, Induces Ferroptosis and Suppresses Tumor Growth in Triple-Negative Breast Cancer Cells","volume":"85","author":"Du","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Malfa, G.A., Tomasello, B., Acquaviva, R., Genovese, C., La Mantia, A., Cammarata, F.P., Ragusa, M., Renis, M., and Di Giacomo, C. (2019). Betula Etnensis Raf. (Betulaceae) Extract Induced HO-1 Expression and Ferroptosis Cell Death in Human Colon Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112723"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kim, H.N., Park, G.H., Park, S.B., Kim, J.D., Eo, H.J., Son, H.-J., Song, J.H., and Jeong, J.B. (2019). Extracts from Sageretia Thea Reduce Cell Viability through Inducing Cyclin D1 Proteasomal Degradation and HO-1 Expression in Human Colorectal Cancer Cells. BMC Complement. Altern. Med., 19.","DOI":"10.1186\/s12906-019-2453-4"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1142\/S0192415X16500580","article-title":"Forsythiae Fructus Inhibits B16 Melanoma Growth Involving MAPKs\/Nrf2\/HO-1 Mediated Anti-Oxidation and Anti-Inflammation","volume":"44","author":"Bao","year":"2016","journal-title":"Am. J. Chin. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3469840","DOI":"10.1155\/2020\/3469840","article-title":"Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells","volume":"2020","author":"Li","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6896790","DOI":"10.1155\/2023\/6896790","article-title":"Curcumin Induces Ferroptosis in Follicular Thyroid Cancer by Upregulating HO-1 Expression","volume":"2023","author":"Chen","year":"2023","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"114154","DOI":"10.1016\/j.biopha.2022.114154","article-title":"Abietic Acid Induces Ferroptosis via the Activation of the HO-1 Pathway in Bladder Cancer Cells","volume":"158","author":"Xu","year":"2023","journal-title":"Biomed. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"710978","DOI":"10.3389\/fphar.2021.710978","article-title":"Nicardipine Inhibits Breast Cancer Migration via Nrf2\/HO-1 Axis and Matrix Metalloproteinase-9 Regulation","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cardile, A., Zanr\u00e8, V., Campagnari, R., Asson, F., Addo, S.S., Orlandi, E., and Menegazzi, M. (2023). Hyperforin Elicits Cytostatic\/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-\u039aB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021263"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"208","DOI":"10.4161\/cc.26971","article-title":"Activities of Multiple Cancer-Related Pathways Are Associated with BRAF Mutation and Predict the Resistance to BRAF\/MEK Inhibitors in Melanoma Cells","volume":"13","author":"Liu","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"430","DOI":"10.37358\/RC.20.4.8084","article-title":"Melanin Quantification by Chemical Methods in Healthy and Melanoma Cell Lines Correlated with the Importance in the Development of Melanoma","volume":"71","author":"Bratu","year":"2020","journal-title":"Rev. Chim."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"842496","DOI":"10.3389\/fonc.2022.842496","article-title":"Melanoma, Melanin, and Melanogenesis: The Yin and Yang Relationship","volume":"12","author":"Slominski","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1002\/ijc.33262","article-title":"Loss of the Cystine\/Glutamate Antiporter in Melanoma Abrogates Tumor Metastasis and Markedly Increases Survival Rates of Mice","volume":"147","author":"Sato","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1186\/s12951-022-01663-8","article-title":"Ferroptosis Assassinates Tumor","volume":"20","author":"Luo","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.bbagen.2011.10.013","article-title":"Regulation of Iron Transport and the Role of Transferrin","volume":"1820","author":"Gkouvatsos","year":"2012","journal-title":"Biochim. Biophys. Acta\u2014Gen. Subj."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3164\/jcbn.21-82","article-title":"Intracellular Ferritin Heavy Chain Plays the Key Role in Artesunate-Induced Ferroptosis in Ovarian Serous Carcinoma Cells","volume":"71","author":"Koike","year":"2022","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3008","DOI":"10.1634\/stemcells.2008-0601","article-title":"The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma","volume":"26","author":"Rappa","year":"2008","journal-title":"Stem Cells"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"C709","DOI":"10.1152\/ajpcell.00212.2015","article-title":"The Emerging Roles of Oct4 in Tumor-Initiating Cells","volume":"309","author":"Wang","year":"2015","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"041004","DOI":"10.1088\/1478-3975\/ab157a","article-title":"Epithelial-to-Mesenchymal Transition: Lessons from Development, Insights into Cancer and the Potential of EMT-Subtype Based Therapeutic Intervention","volume":"16","author":"Antony","year":"2019","journal-title":"Phys Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s00109-015-1266-2","article-title":"Inhibition of UPAR-TGF\u03b2 Crosstalk Blocks MSC-Dependent EMT in Melanoma Cells","volume":"93","author":"Laurenzana","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12935-023-02862-5","article-title":"MMP2 Is a Immunotherapy Related Biomarker and Correlated with Cancer-Associated Fibroblasts Infiltrate in Melanoma","volume":"23","author":"Peng","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brankiewicz, A., Trzos, S., Mro\u017cek, M., Opydo, M., Szostak, E., Dziurka, M., Tuleja, M., \u0141oboda, A., and Poche\u0107, E. (2023). Cytotoxic and Antioxidant Activity of Hypericum perforatum L. Extracts against Human Melanoma Cells from Different Stages of Cancer Progression, Cultured under Normoxia and Hypoxia. Molecules, 28.","DOI":"10.3390\/molecules28031509"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"104642","DOI":"10.1016\/j.yexmp.2021.104642","article-title":"Dual Role of Heme Iron in Cancer; Promotor of Carcinogenesis and an Inducer of Tumour Suppression","volume":"120","author":"Gamage","year":"2021","journal-title":"Exp. Mol. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1165\/rcmb.2006-0340TR","article-title":"How Many Transcription Factors Does It Take to Turn on the Heme Oxygenase-1 Gene?","volume":"36","author":"Alam","year":"2007","journal-title":"Am. J. Respir Cell Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ghareghomi, S., Moosavi-Movahedi, F., Saso, L., Habibi-Rezaei, M., Khatibi, A., Hong, J., and Moosavi-Movahedi, A.A. (2023). Modulation of Nrf2\/HO-1 by Natural Compounds in Lung Cancer. Antioxidants, 12.","DOI":"10.3390\/antiox12030735"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"107664","DOI":"10.1016\/j.pharmthera.2020.107664","article-title":"NRF2 in Human Neoplasm: Cancer Biology and Potential Therapeutic Target","volume":"217","author":"Liu","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"102726","DOI":"10.1016\/j.redox.2023.102726","article-title":"The KEAP1-NRF2 Pathway: Targets for Therapy and Role in Cancer","volume":"63","author":"Adinolfi","year":"2023","journal-title":"Redox Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.cell.2019.06.005","article-title":"BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis","volume":"178","author":"Wiel","year":"2019","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.2353\/ajpath.2006.051365","article-title":"Overexpression of Heme Oxygenase-1 in Murine Melanoma: Increased Proliferation and Viability of Tumor Cells, Decreased Survival of Mice","volume":"169","author":"Was","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kusienicka, A., Bukowska-Strakova, K., Cie\u015bla, M., Nowak, W.N., Bronisz-Budzy\u0144ska, I., Seretny, A., \u017bukowska, M., Je\u017c, M., Krutyho\u0142owa, R., and Taha, H. (2022). Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers. IJMS, 23.","DOI":"10.3390\/ijms23073596"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.tcb.2015.10.014","article-title":"Ferroptosis: Death by Lipid Peroxidation","volume":"26","author":"Yang","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Chen, M., Shi, Z., Sun, Y., Ning, H., Gu, X., and Zhang, L. (2023). Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021607"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Shibata, Y., Yasui, H., Higashikawa, K., Miyamoto, N., and Kuge, Y. (2019). Erastin, a Ferroptosis-Inducing Agent, Sensitized Cancer Cells to X-Ray Irradiation via Glutathione Starvation in Vitro and in Vivo. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225931"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-019-1707-0","article-title":"FSP1 Is a Glutathione-Independent Ferroptosis Suppressor","volume":"575","author":"Doll","year":"2019","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41586-019-1705-2","article-title":"The CoQ Oxidoreductase FSP1 Acts Parallel to GPX4 to Inhibit Ferroptosis","volume":"575","author":"Bersuker","year":"2019","journal-title":"Nature"},{"key":"ref_60","first-page":"974","article-title":"Role of Dietary Iron Revisited: In Metabolism, Ferroptosis and Pathophysiology of Cancer","volume":"12","author":"Pandrangi","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.bbrc.2021.04.024","article-title":"Dioscin Induces Ferroptosis and Synergistic Cytotoxicity with Chemotherapeutics in Melanoma Cells","volume":"557","author":"Xie","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"146460","DOI":"10.1016\/j.gene.2022.146460","article-title":"Sinapine Induced Ferroptosis in Non-Small Cell Lung Cancer Cells by Upregulating Transferrin\/Transferrin Receptor and Downregulating SLC7A11","volume":"827","author":"Shao","year":"2022","journal-title":"Gene"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Chen, F., Cai, X., Kang, R., Liu, J., and Tang, D. (2023). Autophagy-Dependent Ferroptosis in Cancer. Antioxid. Redox Signal.","DOI":"10.1089\/ars.2022.0202"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1080\/15548627.2016.1187366","article-title":"Autophagy Promotes Ferroptosis by Degradation of Ferritin","volume":"12","author":"Hou","year":"2016","journal-title":"Autophagy"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/pcmr.13009","article-title":"The Role of Ferroptosis in Melanoma","volume":"35","author":"Talty","year":"2022","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3275","DOI":"10.1038\/s41388-018-0205-4","article-title":"AXL\/AKT Axis Mediated-Resistance to BRAF Inhibitor Depends on PTEN Status in Melanoma","volume":"37","author":"Zuo","year":"2018","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1158\/1078-0432.CCR-16-0869","article-title":"Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer","volume":"23","author":"Miller","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Shao, H., Teramae, D., and Wells, A. (2023). Axl Contributes to Efficient Migration and Invasion of Melanoma Cells. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0283749"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1097\/CMR.0000000000000124","article-title":"Inhibition of Tumor Growth by \u03b2-Elemene through Downregulation of the Expression of UPA, UPAR, MMP-2, and MMP-9 in a Murine Intraocular Melanoma Model","volume":"25","author":"Shi","year":"2015","journal-title":"Melanoma Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.tins.2023.01.003","article-title":"How Cancer Hijacks the Body\u2019s Homeostasis through the Neuroendocrine System","volume":"46","author":"Slominski","year":"2023","journal-title":"Trends Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Menegazzi, M., Masiello, P., and Novelli, M. (2020). Anti-Tumor Activity of Hypericum Perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics. Antioxidants, 10.","DOI":"10.3390\/antiox10010018"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/7\/1369\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:03:36Z","timestamp":1760126616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/7\/1369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,30]]},"references-count":71,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["antiox12071369"],"URL":"https:\/\/doi.org\/10.3390\/antiox12071369","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,30]]}}}