{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:17:07Z","timestamp":1784866627415,"version":"3.55.0"},"reference-count":110,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005888","name":"Medical University of Lodz","doi-asserted-by":"publisher","award":["503\/3-066-02\/503-31-001"],"award-info":[{"award-number":["503\/3-066-02\/503-31-001"]}],"id":[{"id":"10.13039\/501100005888","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science Center","award":["2023\/07\/X\/NZ3\/01404"],"award-info":[{"award-number":["2023\/07\/X\/NZ3\/01404"]}]},{"name":"National Science Center","award":["2024\/08\/X\/NZ7\/01232"],"award-info":[{"award-number":["2024\/08\/X\/NZ7\/01232"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC50 &lt; 35 \u03bcM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1\/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone\/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer.<\/jats:p>","DOI":"10.3390\/molecules31030534","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multifaceted Anticancer Activity of Flavanone\/Chromanone Intermediates for Five-Membered Heterocyclic Derivatives: Targeting Oxidative Stress, Apoptosis, and MAPK Signaling in Colorectal Cancer"],"prefix":"10.3390","volume":"31","author":[{"given":"Pawel","family":"Hikisz","sequence":"first","affiliation":[{"name":"Department of Oncobiology and Epigenetics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0119-599X","authenticated-orcid":false,"given":"Angelika A.","family":"Adamus-Grabicka","sequence":"additional","affiliation":[{"name":"Department of Bioinorganic Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9949-8723","authenticated-orcid":false,"given":"Elzbieta","family":"Budzisz","sequence":"additional","affiliation":[{"name":"Department of the Chemistry of Cosmetic Raw Materials, Medical University of Lodz, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/ijc.35278","article-title":"The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the cancer burden worldwide","volume":"156","author":"Filho","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1159\/000543921","article-title":"Colorectal Cancer: Epidemiology, Risk Factors, and Public Health Strategies","volume":"106","author":"Matsuda","year":"2025","journal-title":"Digestion"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tsokkou, S., Konstantinidis, I., Papakonstantinou, M., Chatzikomnitsa, P., Liampou, E., Toutziari, E., Giakoustidis, D., Bangeas, P., Papadopoulos, V., and Giakoustidis, A. (2025). Sex Differences in Colorectal Cancer: Epidemiology, Risk Factors, and Clinical Outcomes. J. Clin. Med., 14.","DOI":"10.3390\/jcm14155539"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6115","DOI":"10.1111\/ijfs.15270","article-title":"Consumption of processed red meat and its impact on human health: A review","volume":"56","author":"Libera","year":"2021","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1016\/j.tjnut.2025.08.030","article-title":"Processed Meat Health Risks: Pathways and Dietary Solutions","volume":"155","author":"Bajinka","year":"2025","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107540","DOI":"10.1016\/j.cdnut.2025.107540","article-title":"Meat Consumption in Relation to Colorectal Cancer Incidence in Anatomical Subsites in the National Institutes of Health-AARP Diet and Health Study","volume":"9","author":"Zouiouich","year":"2025","journal-title":"Curr. Dev. Nutr."},{"key":"ref_7","first-page":"1","article-title":"The role of TP53, APC, and KRAS gene polymorphisms in the development of colorectal cancer","volume":"16","year":"2025","journal-title":"Biomed. Istra\u017e."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1111\/cas.70187","article-title":"Impact of TP53, KRAS, and APC Mutations on Neoadjuvant Chemotherapy Outcomes in Locally Advanced Rectal Cancer","volume":"116","author":"Takeda","year":"2025","journal-title":"Cancer Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9663","DOI":"10.1007\/s11033-023-08809-3","article-title":"Cancer treatment therapies: Traditional to modern approaches to combat cancers","volume":"50","author":"Kaur","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Eslami, M., Memarsadeghi, O., Davarpanah, A., Arti, A., Nayernia, K., and Behnam, B. (2024). Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010183"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e15734064384513","DOI":"10.2174\/0115734064384513250624043626","article-title":"Promising Flavone Derivatives as Anticancer Agents","volume":"21","author":"Patil","year":"2025","journal-title":"Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pyo, Y., Kwon, K.H., and Jung, Y.J. (2024). Anticancer Potential of Flavonoids: Their Role in Cancer Prevention and Health Benefits. Foods, 13.","DOI":"10.3390\/foods13142253"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Musaogullari, A., Mandato, A., and Chai, Y.-C. (2020). Role of Glutathione Depletion and Reactive Oxygen Species Generation on Caspase-3 Activation: A Study with the Kinase Inhibitor Staurosporine. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00998"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ramawat, K.G., and M\u00e9rillon, J.-M. (2025). Minor Flavonoids (Chalcones, Flavanones, Dihydrochalcones, and Aurones). Natural Products, Springer.","DOI":"10.1007\/978-3-642-36202-6"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2412029","DOI":"10.4014\/jmb.2412.12029","article-title":"Naringenin Inhibits Colorectal Cancer associated with a High-Fat Diet through Modulation of Gut Microbiota and IL-6\/STAT3 Pathway","volume":"35","author":"Sun","year":"2025","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s11655-024-4113-x","article-title":"Hesperidin Suppressed Colorectal Cancer through Inhibition of Glycolysis","volume":"31","author":"Sun","year":"2025","journal-title":"Chin. J. Integr. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liga, S., Paul, C., and P\u00e9ter, F. (2023). Flavonoids: Overview of Biosynthesis, Biological Activity, and Current Extraction Techniques. Plants, 12.","DOI":"10.3390\/plants12142732"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: An overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kang, M.-J., Lee, K.-R., Choi, Y.-J., and Chae, Y.-J. (2024). Identification of flavonol derivatives inhibiting MDR1: A strategy to overcome multidrug resistance in cancer. Nat. Prod. Res., 1\u20139.","DOI":"10.1080\/14786419.2024.2420333"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"La Monica, G., Alamia, F., Bono, A., Lauria, A., and Martorana, A. (2024). Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues. Molecules, 29.","DOI":"10.3390\/molecules29122813"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e202401899","DOI":"10.1002\/cbdv.202401899","article-title":"Flavonoid Based Development of Synthetic Drugs: Chemistry and Biological Activities","volume":"22","author":"Nath","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mihajlovi\u0107, L.E., Trif, M., and \u017divkovi\u0107, M.B. (2025). Metal Complexes with Hydroxyflavones: A Study of Anticancer and Antimicrobial Activities. Inorganics, 13.","DOI":"10.3390\/inorganics13080250"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"117791","DOI":"10.1016\/j.bmc.2024.117791","article-title":"Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry","volume":"109","author":"Bono","year":"2024","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Matiadis, D., and Sagnou, M. (2020). Pyrazoline Hybrids as Promising Anticancer Agents: An Up-to-Date Overview. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155507"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1016\/j.ccr.2009.06.015","article-title":"Biological activity of metal ions complexes of chromones, coumarins and flavones","volume":"253","author":"Grazul","year":"2009","journal-title":"Coord. Chem. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Adamus-Grabicka, A.A., Markowicz-Piasecka, M., Cie\u015blak, M., Kr\u00f3lewska-Goli\u0144ska, K., Hikisz, P., Kusz, J., Ma\u0142ecka, M., and Budzisz, E. (2020). Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues. Molecules, 25.","DOI":"10.3390\/molecules25071613"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Adamus-Grabicka, A.A., Da\u015bko, M., Hikisz, P., Kusz, J., Malecka, M., and Budzisz, E. (2022). Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116061"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hikisz, P., Wawrzyniak, P., Adamus-Grabicka, A.A., Jacenik, D., and Budzisz, E. (2024). Evaluation of In Vitro Biological Activity of Flavanone\/Chromanone Derivatives: Molecular Analysis of Anticancer Mechanisms in Colorectal Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312985"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bondar, D., and Karpichev, Y. (2024). Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions. Biomolecules, 14.","DOI":"10.3390\/biom14101269"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"108188","DOI":"10.1016\/j.bioorg.2025.108188","article-title":"Role of PARP-1 structural and functional features in PARP-1 inhibitors development","volume":"156","author":"Merkuryev","year":"2025","journal-title":"Bioorg. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11693","DOI":"10.3390\/molecules171011693","article-title":"Synthetic flavanones augment the anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)","volume":"17","author":"Szliszka","year":"2012","journal-title":"Molecules"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/rda.12549","article-title":"Cleaved PARP-1, an Apoptotic Marker, can be Detected in Ram Spermatozoa","volume":"50","author":"Casao","year":"2015","journal-title":"Reprod. Domest. Anim."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103450","DOI":"10.1016\/j.bioorg.2019.103450","article-title":"The synthetic flavanone 6-methoxy-2-(naphthalen-1-yl)chroman-4-one induces apoptosis and activation of the MAPK pathway in human U-937 leukaemia cells","volume":"94","author":"Saavedra","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11626-017-0209-3","article-title":"Caspase-dependent apoptosis induced by two synthetic halogenated flavanones, 3\u2032,7-dichloroflavanone and 3\u2032,6-dichloroflavanone, on human breast and prostate cancer cells","volume":"54","author":"Safavi","year":"2018","journal-title":"In Vitro Cell. Dev. Biol. Anim."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Su, C., Haskins, A.H., Omata, C., Aizawa, Y., and Kato, T.A. (2017). PARP Inhibition by Flavonoids Induced Selective Cell Killing to BRCA2-Deficient Cells. Pharmaceuticals, 10.","DOI":"10.3390\/ph10040080"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/ptr.5540","article-title":"Antitumor Activity of Total Flavonoids from Daphne genkwa in Colorectal Cancer","volume":"30","author":"Du","year":"2016","journal-title":"Phytother. Res."},{"key":"ref_37","first-page":"E4061","article-title":"PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression","volume":"115","author":"Seiwert","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e79679","DOI":"10.5812\/jjnpp.79679","article-title":"The Effects of Doxorubicin, Ethanol Extract and Flavonoid-rich Fraction of Euphorbia Splendida Mobayen on the PARP Level, and APC Gene Expression in HT-29 Human Colon Cancer Cell Line","volume":"15","author":"Aein","year":"2020","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.annonc.2020.05.027","article-title":"The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer","volume":"31","author":"Mauri","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mitra, S., Nguyen, L.N., Akter, M., Park, G., Choi, E.H., and Kaushik, N.K. (2019). Impact of ROS Generated by Chemical, Physical, and Plasma Techniques on Cancer Attenuation. Cancers, 11.","DOI":"10.3390\/cancers11071030"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41573-024-00979-4","article-title":"Targeting ROS in cancer: Rationale and strategies","volume":"23","author":"Glorieux","year":"2024","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ahamad, M.S., Siddiqui, S., Jafri, A., Ahmad, S., Afzal, M., and Arshad, M. (2014). Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110003"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.7150\/ijbs.85443","article-title":"Promotion of ROS-mediated apoptosis, G2\/M arrest, and autophagy by naringenin in non-small cell lung cancer","volume":"20","author":"Chang","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1002\/ptr.70058","article-title":"Association of Total Flavonoid and Flavonoid Subclass Intake with Cancer-Related and All-Cause Mortality Among Cancer Patients","volume":"39","author":"Jia","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Chobot, V., Hadacek, F., Bachmann, G., Weckwerth, W., and Kubicova, L. (2020). In Vitro Evaluation of Pro- and Antioxidant Effects of Flavonoid Tricetin in Comparison to Myricetin. Molecules, 25.","DOI":"10.3390\/molecules25245850"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1021\/tx060157q","article-title":"Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression","volume":"19","author":"Boerboom","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_47","first-page":"161","article-title":"Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion","volume":"31","author":"Kachadourian","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s10120-021-01159-8","article-title":"Apatinib induced ferroptosis by lipid peroxidation in gastric cancer","volume":"24","author":"Zhao","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2412593","DOI":"10.1002\/advs.202412593","article-title":"Susceptibility of Mitophagy-Deficient Tumors to Ferroptosis Induction by Relieving the Suppression of Lipid Peroxidation","volume":"12","author":"Liu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15642","DOI":"10.1021\/jp1014719","article-title":"Interplay between structure and fluidity of model lipid membranes under oxidative attack","volume":"114","author":"Tai","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"G\u00fcnther, G., Berr\u00edos, E., Pizarro, N., Vald\u00e9s, K., Montero, G., Arriagada, F., and Morales, J. (2015). Flavonoids in Microheterogeneous Media, Relationship between Their Relative Location and Their Reactivity towards Singlet Oxygen. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129749"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"158","DOI":"10.7455\/ijfs\/6.2.2017.a4","article-title":"Impact of selected polyphenolics on the structural properties of model lipid membranes\u2014A review","volume":"6","author":"Ota","year":"2017","journal-title":"Int. J. Food Stud."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10561","DOI":"10.1038\/s41598-024-61037-y","article-title":"Structural investigation of interactions between halogenated flavonoids and the lipid membrane along with their role as cytotoxic agents","volume":"14","author":"Dudek","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Endale, H.T., Tesfaye, W., and Mengstie, T.A. (2023). ROS induced lipid peroxidation and their role in ferroptosis. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1226044"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.bbrc.2016.10.086","article-title":"Lipid peroxidation in cell death","volume":"482","author":"Gaschler","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5080843","DOI":"10.1155\/2019\/5080843","article-title":"Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis","volume":"2019","author":"Su","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tox.2012.12.014","article-title":"Role for membrane remodeling in cell death: Implication for health and disease","volume":"304","author":"Tekpli","year":"2013","journal-title":"Toxicology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/s41419-020-03118-0","article-title":"Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis","volume":"11","author":"Wiernicki","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Chatgilialoglu, C. (2024). Biomarkers of Oxidative and Radical Stress. Biomolecules, 14.","DOI":"10.3390\/biom14020194"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.plipres.2015.04.003","article-title":"Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment","volume":"59","author":"Busquets","year":"2015","journal-title":"Prog. Lipid Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.molcel.2023.11.040","article-title":"The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death","volume":"84","author":"Ai","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e107521","DOI":"10.1590\/fst.107521","article-title":"Combinations of traditional kombucha tea with medicinal plant extracts for enhancement of beneficial substances and activation of apoptosis signaling pathways in colorectal cancer cells","volume":"42","author":"Kaewkod","year":"2022","journal-title":"Food Sci. Technol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9960","DOI":"10.1021\/acs.jafc.8b02656","article-title":"Reactive Oxygen Species and p53 Mediated Activation of p38 and Caspases is Critically Involved in Kaempferol Induced Apoptosis in Colorectal Cancer Cells","volume":"66","author":"Choi","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9755\/ejfa.2023.3204","article-title":"Polyphenol galangin induces the ROS and ER stress-mediated intrinsic and extrinsic apoptotic pathways towards human colon carcinoma HCT-116 cells","volume":"12","author":"Wang","year":"2023","journal-title":"Emir. J. Food Agric."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wongkaewkhiaw, S., Wongrakpanich, A., Krobthong, S., Saengsawang, W., Chairoungdua, A., and Boonmuen, N. (2022). Induction of apoptosis in human colorectal cancer cells by nanovesicles from fingerroot (Boesenbergia rotunda (L.) Mansf.). PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0266044"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1177\/0960327119882986","article-title":"Cyclization of flavokawain B reduces its activity against human colon cancer cells","volume":"39","author":"Janeczko","year":"2020","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Latif, A., Gonda, T., K\u00fasz, N., Kulm\u00e1ny, \u00c1., Zupk\u00f3, I., and Hunyadi, A. (2018). Synthesis and evaluation cytotoxic and antioxidant effects of naringenin oxime relative to naringenin on human cancer cell lines. Fiatal Gy\u00f3gyn\u00f6v\u00e9nykutat\u00f3k F\u00f3ruma. Fiatal Gy\u00f3gyn\u00f6v\u00e9nykutat\u00f3k F\u00f3ruma, Szeged, Hungary, 30 November 2018, Magyar Gy\u00f3gyszer\u00e9sztudom\u00e1nyi T\u00e1rsas\u00e1g Gy\u00f3gyn\u00f6v\u00e9ny Szakoszt\u00e1lya. 12p.","DOI":"10.14232\/fgykf.2018.b3"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s13167-025-00407-6","article-title":"Targeting the MAPK signaling pathway: Implications and prospects of flavonoids in 3P medicine as modulators of cancer cell plasticity and therapeutic resistance in breast cancer patients","volume":"16","author":"Kubatka","year":"2025","journal-title":"EPMA J."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Zhou, L., Zhang, J., Zhao, K., Chen, B., and Sun, Z. (2025). Natural products modulating MAPK for CRC treatment: A promising strategy. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1514486"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"932","DOI":"10.2174\/1568009621666211103113339","article-title":"The Therapeutic Potential of MAPK\/ERK Inhibitors in the Treatment of Colorectal Cancer","volume":"21","author":"Pashirzad","year":"2021","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"923","DOI":"10.18311\/jnr\/2023\/31321","article-title":"Computational Analysis Depicting Potency of Phytochemicals to Target MAPK Signalling Pathway in Breast Cancer","volume":"23","author":"Balkrishna","year":"2023","journal-title":"J. Nat. Remedies"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"247","DOI":"10.2174\/187153011796429790","article-title":"Attenuation of ERK\/RSK2-driven NF\u03baB gene expression and cancer cell proliferation by kurarinone, a lavandulyl flavanone isolated from Sophora flavescens ait. roots","volume":"11","author":"Berghe","year":"2011","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1158\/1535-7163.MCT-14-0634","article-title":"Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway","volume":"14","author":"Liu","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.phymed.2008.11.006","article-title":"Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf\/MEK\/ERK pathway in MCF-7 human breast cancer cells","volume":"16","author":"Kim","year":"2009","journal-title":"Phytomedicine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1002\/jcp.21061","article-title":"IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells","volume":"212","author":"Lin","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1016\/j.biochi.2013.07.021","article-title":"Luteolin 8-C-\u03b2-fucopyranoside inhibits invasion and suppresses TPA-induced MMP-9 and IL-8 via ERK\/AP-1 and ERK\/NF-\u03baB signaling in MCF-7 breast cancer cells","volume":"95","author":"Park","year":"2013","journal-title":"Biochimie"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.4314\/tjpr.v20i11.15","article-title":"Brassica juncea polysaccharides induce apoptosis of colorectal cancer cells via mitochondrial- and caspasedependent apoptosis pathways","volume":"20","author":"Peng","year":"2021","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Baek, J.-Y., Kwak, J.-E., and Ahn, M.-R. (2024). Eriocitrin Inhibits Angiogenesis by Targeting VEGFR2-Mediated PI3K\/AKT\/mTOR Signaling Pathways. Nutrients, 16.","DOI":"10.3390\/nu16071091"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4540","DOI":"10.1111\/j.1582-4934.2008.00575.x","article-title":"Synergistic promotion of breast cancer cells death by targeting molecular chaperone GRP78 and heat shock protein 70","volume":"13","author":"Li","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1080\/01635581.2015.1073763","article-title":"Inhibitory Effects of Isorhamnetin on the Invasion of Human Breast Carcinoma Cells by Downregulating the Expression and Activity of Matrix Metalloproteinase-2\/9","volume":"67","author":"Li","year":"2015","journal-title":"Nutr. Cancer"},{"key":"ref_81","first-page":"1301","article-title":"Analysis of cell growth inhibitory effects of catechin through MAPK in human breast cancer cell line T47D","volume":"21","author":"Deguchi","year":"2002","journal-title":"Int. J. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1002\/med.21574","article-title":"JNK signaling in cancer cell survival","volume":"39","author":"Wu","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Kim, K.M., and Jung, J. (2020). Upregulation of G Protein-Coupled Estrogen Receptor by Chrysin-Nanoparticles Inhibits Tumor Proliferation and Metastasis in Triple Negative Breast Cancer Xenograft Model. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.560605"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Lim\u00f3n, A., Joaquin, M., Caballero, M., Posas, F., and de Nadal, E. (2020). The p38 Pathway: From Biology to Cancer Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061913"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ma, Y.-T., Li, C., Shen, Y., You, W.-H., Han, M.-X., Mu, Y.-F., and Han, F.-J. (2025). Mechanisms of the JNK\/p38 MAPK signaling pathway in drug resistance in ovarian cancer. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1533352"},{"key":"ref_86","first-page":"2306","article-title":"NOX4\/ROS mediate ethanol-induced apoptosis via MAPK signal pathway in L-02 cells","volume":"41","author":"Yang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"Wagner","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1038\/sj.onc.1210421","article-title":"MAP kinase signalling pathways in cancer","volume":"26","author":"Dhillon","year":"2007","journal-title":"Oncogene"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Seo, S.Y., Joo, S.H., Lee, S.-O., Yoon, G., Cho, S.-S., Choi, Y.H., Park, J.W., and Shim, J.-H. (2024). Activation of p38 and JNK by ROS Contributes to Deoxybouvardin-Mediated Intrinsic Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells. Antioxidants, 13.","DOI":"10.3390\/antiox13070866"},{"key":"ref_90","first-page":"959","article-title":"Opposing role of JNK-p38 kinase and ERK1\/2 in hydrogen peroxide-induced oxidative damage of human trophoblast-like JEG-3 cells","volume":"7","author":"Tang","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.toxlet.2013.02.003","article-title":"JNK and p38 MAPK regulate oxidative stress and the inflammatory response in chlorpyrifos-induced apoptosis","volume":"218","author":"Ki","year":"2013","journal-title":"Toxicol. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Gonzalez-Donquiles, C., Alonso-Molero, J., Fernandez-Villa, T., Vilorio-Marqu\u00e9s, L., Molina, A.J., and Mart\u00edn, V. (2017). The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177549"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"15330338221105736","DOI":"10.1177\/15330338221105736","article-title":"Role of NRF2 in Colorectal Cancer Prevention and Treatment","volume":"21","author":"Li","year":"2022","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5985","DOI":"10.2147\/JIR.S479794","article-title":"The Dual Role of NRF2 in Colorectal Cancer: Targeting NRF2 as a Potential Therapeutic Approach","volume":"17","author":"Hu","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"O\u2019Cathail, S.M., Wu, C.-H., Thomas, R., Hawkins, M.A., Maughan, T.S., and Lewis, A. (2021). NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch. Antioxidants, 10.","DOI":"10.3390\/antiox10091380"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s41419-022-05512-2","article-title":"Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis","volume":"13","author":"Hsu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Torrente, L., Maan, G., Oumkaltoum Rezig, A., Quinn, J., Jackson, A., Grilli, A., Casares, L., Zhang, Y., Kulesskiy, E., and Saarela, J. (2020). High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro. Biomolecules, 10.","DOI":"10.3390\/biom10101365"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"41","DOI":"10.15430\/JCP.2021.26.1.41","article-title":"Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane\/Dextran Sulfate Sodium-Treatment in Female Mice","volume":"26","author":"Song","year":"2021","journal-title":"J. Cancer Prev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1039\/C4FO01164C","article-title":"Naringin protects against anoxia\/reoxygenation-induced apoptosis in H9c2 cells via the Nrf2 signaling pathway","volume":"6","author":"Chen","year":"2015","journal-title":"Food Funct."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Jang, C.H., Moon, N., Oh, J., and Kim, J.-S. (2019). Luteolin Shifts Oxaliplatin-Induced Cell Cycle Arrest at G0\/G1 to Apoptosis in HCT116 Human Colorectal Carcinoma Cells. Nutrients, 11.","DOI":"10.3390\/nu11040770"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/s41598-018-37173-7","article-title":"Rosemary (Rosmarinus officinalis) extract causes ROS-induced necrotic cell death and inhibits tumor growth In Vivo","volume":"9","author":"Cifuentes","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1208\/s12248-010-9239-4","article-title":"Anti-inflammatory\/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis","volume":"13","author":"Wu","year":"2010","journal-title":"AAPS J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jff.2019.04.037","article-title":"Strawberry tree honey as a new potential functional food. Part 2: Strawberry tree honey increases ROS generation by suppressing Nrf2-ARE and NF-\u03baB signaling pathways and decreases metabolic phenotypes and metastatic activity in colon cancer cells","volume":"57","author":"Afrin","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"10054","DOI":"10.1021\/acsomega.0c06345","article-title":"Design, Synthesis, Characterization, and Crystal Structure Studies of Nrf2 Modulators for Inhibiting Cancer Cell Growth In Vitro and In Vivo","volume":"6","author":"Chikkegowda","year":"2021","journal-title":"ACS Omega"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1073\/pnas.1014275108","article-title":"Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism","volume":"108","author":"Ren","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41420-024-02278-8","article-title":"Free radicals and their impact on health and antioxidant defenses: A review","volume":"11","author":"Chandimali","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1007\/s00204-013-1034-4","article-title":"Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis","volume":"87","author":"Sinha","year":"2013","journal-title":"Arch. Toxicol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/3\/534\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:31Z","timestamp":1770122791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/3\/534"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,3]]},"references-count":110,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["molecules31030534"],"URL":"https:\/\/doi.org\/10.3390\/molecules31030534","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,3]]}}}