{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:13:11Z","timestamp":1791893591851,"version":"4.3.4"},"reference-count":70,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Oral squamous cell carcinoma (OSCC) ranks 16th worldwide as the most common type of malignancy in head and neck cancer globally, and addressing it has been an ongoing but difficult pursuit, as treatment resistance is commonly reported. Hence, employing multiple cell death pathways is an emerging strategy in overcoming treatment resistance in OSCC. We investigate here the effect of heteronemin, a marine sesterterpenoid isolated from sponges, for its anti-cancer potential, hypothesizing that it can induce non-apoptotic cell death pathways to overcome apoptosis-resistant cells and elucidate the underlying mechanisms involved. Our results show that heteronemin significantly kills cancer cells via the induction of the intrinsic apoptotic pathway. It also triggers ferroptosis, down-regulating glutathione peroxidase 4 (GPX4) and upregulating markers of lipid peroxidation such as 4-hydroxynonenal and malondialdehyde. We demonstrate that increasing reactive oxygen species generation plays a central role in triggering these pathways. ensuring the death of the cancer cells despite a compensation attempt via inducing autophagy and modulating Nrf2. Our study is the first to demonstrate the complex but interesting role of heteronemin in killing OSCC cells: inducing apoptosis and switching to ferroptosis as the cells attempt to survive. It also inhibits protective autophagy, leaving OSCC cells incapable of protecting themselves from imminent death. This complex mechanism adds to the existing knowledge on the mechanism of heteronemin as a strong therapeutic compound to treat OSCC cells.<\/jats:p>","DOI":"10.2478\/aite-2026-0016","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T18:57:49Z","timestamp":1783191469000},"source":"Crossref","is-referenced-by-count":1,"title":["Heteronemin, a Scalarane Sesterterpenoid, Activates Apoptosis and Non-Apoptotic Ferroptosis and Inhibits Cytoprotective Autophagy in Oral Cancer Cells"],"prefix":"10.2478","volume":"74","author":[{"given":"Rovelyn","family":"Gallego","sequence":"first","affiliation":[{"name":"PhD Program in Life Sciences, College of Life Science , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Biology, College of Mathematics and Natural Sciences , Caraga State University , Butuan City , Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Tzu","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Kai","family":"Hsu","sequence":"additional","affiliation":[{"name":"PhD Program in Life Sciences, College of Life Science , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hua","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciao-Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En-De","family":"Shu","sequence":"additional","affiliation":[{"name":"PhD Program in Life Sciences, College of Life Science , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Ming","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry , National Chiayi University , Chiayi , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Chin","family":"Lu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Marine Biology , National Dong Hwa University , Pingtung , Taiwan"},{"name":"National Museum of Marine Biology and Aquarium , Pingtung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Chung","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Chi Mei Medical Center , Tainan , Taiwan"},{"name":"Department of Health and Nutrition , Chia Nan University of Pharmacy and Science , Tainan , Taiwan"},{"name":"School of Medicine, College of Medicine , National Sun Yat-Sen University , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-2468","authenticated-orcid":false,"given":"Chien-Chih","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Biological Sciences , National Sun Yat-Sen University , Kaohsiung , Taiwan"},{"name":"Center for Cancer Research , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Drug Development and Value Creation Research Center , Kaohsiung Medical University , Kaohsiung , Taiwan"},{"name":"Department of Medical Research , Kaohsiung Medical University Hospital , Kaohsiung , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"2026072522431533278_j_aite-2026-0016_ref_001","doi-asserted-by":"crossref","unstructured":"Almangush A, Leivo I, M\u00e4kitie AA (2021) Biomarkers for immunotherapy of oral squamous cell carcinoma: Current status and challenges. Front Oncol 11:616629. https:\/\/doi.org\/10.3389\/fonc.2021.616629","DOI":"10.3389\/fonc.2021.616629"},{"key":"2026072522431533278_j_aite-2026-0016_ref_002","doi-asserted-by":"crossref","unstructured":"Bauer G, Zarkovic N (2015) Revealing mechanisms of selective, concentration-dependent potentials of 4-hydroxy-2-nonenal to induce apoptosis in cancer cells through inactivation of membrane-associated catalase. Free Radic Biol Med 81:128\u2013144. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.01.010","DOI":"10.1016\/j.freeradbiomed.2015.01.010"},{"key":"2026072522431533278_j_aite-2026-0016_ref_003","doi-asserted-by":"crossref","unstructured":"Bedoui S, Herold MJ, Strasser A (2020) Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol 21:678\u2013695. https:\/\/doi.org\/10.1038\/s41580-020-0270-8","DOI":"10.1038\/s41580-020-0270-8"},{"key":"2026072522431533278_j_aite-2026-0016_ref_004","doi-asserted-by":"crossref","unstructured":"Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122(Pt 4):437\u2013441. https:\/\/doi.org\/10.1242\/jcs.031682","DOI":"10.1242\/jcs.031682"},{"key":"2026072522431533278_j_aite-2026-0016_ref_005","doi-asserted-by":"crossref","unstructured":"Cao X, Deng X, May WS (2003) Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax. Blood 102:2605\u20132614. https:\/\/doi.org\/10.1182\/blood-2003-01-0211","DOI":"10.1182\/blood-2003-01-0211"},{"key":"2026072522431533278_j_aite-2026-0016_ref_006","doi-asserted-by":"crossref","unstructured":"Cao M, Shi E, Wang H et al. (2022) Personalized targeted therapeutic strategies against oral squamous cell carcinoma. An evidence-based review of literature. Int J Nanomedicine 17:4293\u20134306. https:\/\/doi.org\/10.2147\/ijn.S377816","DOI":"10.2147\/IJN.S377816"},{"key":"2026072522431533278_j_aite-2026-0016_ref_007","doi-asserted-by":"crossref","unstructured":"Carneiro BA, El-Deiry WS (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 17:395\u2013417. https:\/\/doi.org\/10.1038\/s41571-020-0341-y","DOI":"10.1038\/s41571-020-0341-y"},{"key":"2026072522431533278_j_aite-2026-0016_ref_008","doi-asserted-by":"crossref","unstructured":"Chang WT, Bow YD, Fu PJ et al. (2021) A marine terpenoid, heteronemin, induces both the apoptosis and ferroptosis of hepatocellular carcinoma cells and involves the ROS and MAPK pathways. Oxid Med Cell Longev 2021:7689045. https:\/\/doi.org\/10.1155\/2021\/7689045","DOI":"10.1155\/2021\/7689045"},{"key":"2026072522431533278_j_aite-2026-0016_ref_009","doi-asserted-by":"crossref","unstructured":"Chang YC, Tseng SW, Liu LL et al. (2012) Cytotoxic sesterterpenoids from a sponge Hippospongia sp. Mar Drugs 10:987\u2013997. https:\/\/doi.org\/10.3390\/md10050987","DOI":"10.3390\/md10050987"},{"key":"2026072522431533278_j_aite-2026-0016_ref_010","doi-asserted-by":"crossref","unstructured":"Chaudhary AA, Fareed M, Khan SU et al. (2024) Exploring the therapeutic potential of lipid-based nanoparticles in the management of oral squamous cell carcinoma. Explor Target Antitumor Ther 5:1223\u20131246. https:\/\/doi.org\/10.37349\/etat.2024.00272","DOI":"10.37349\/etat.2024.00272"},{"key":"2026072522431533278_j_aite-2026-0016_ref_011","doi-asserted-by":"crossref","unstructured":"Chen TC, Chuang JY, Ko CY et al. (2020) AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-mediated redox homeostasis. Redox Biol 30:101413. https:\/\/doi.org\/10.1016\/j.redox.2019.101413","DOI":"10.1016\/j.redox.2019.101413"},{"key":"2026072522431533278_j_aite-2026-0016_ref_012","doi-asserted-by":"crossref","unstructured":"Cheng MH, Huang HL, Lin YY et al. (2019) BA6 induces apoptosis via stimulation of reactive oxygen species and inhibition of oxidative phosphorylation in human lung cancer cells. Oxid Med Cell Longev 2019:6342104. https:\/\/doi.org\/10.1155\/2019\/6342104","DOI":"10.1155\/2019\/6342104"},{"key":"2026072522431533278_j_aite-2026-0016_ref_013","doi-asserted-by":"crossref","unstructured":"Cheng Y, Li S, Gao L et al. (2021) The molecular basis and therapeutic aspects of cisplatin resistance in oral squamous cell carcinoma. Front Oncol 11:761379. https:\/\/doi.org\/10.3389\/fonc.2021.761379","DOI":"10.3389\/fonc.2021.761379"},{"key":"2026072522431533278_j_aite-2026-0016_ref_014","doi-asserted-by":"crossref","unstructured":"Chen L, Hambright WS, Na R et al. (2015) Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 290:28097\u201328106. https:\/\/doi.org\/10.1074\/jbc.M115.680090","DOI":"10.1074\/jbc.M115.680090"},{"key":"2026072522431533278_j_aite-2026-0016_ref_015","doi-asserted-by":"crossref","unstructured":"Chen Z, Lin H, Wang X et al. (2024b) The application of approaches in detecting ferroptosis. Heliyon 10:e23507. https:\/\/doi.org\/10.1016\/j.heliyon.2023.e23507","DOI":"10.1016\/j.heliyon.2023.e23507"},{"key":"2026072522431533278_j_aite-2026-0016_ref_016","doi-asserted-by":"crossref","unstructured":"Chen R, Zhu S, Zhao R et al. (2024a) Targeting ferroptosis as a potential strategy to overcome the resistance of cisplatin in oral squamous cell carcinoma. Front Pharmacol 15:1402514. https:\/\/doi.org\/10.3389\/fphar.2024.1402514","DOI":"10.3389\/fphar.2024.1402514"},{"key":"2026072522431533278_j_aite-2026-0016_ref_017","doi-asserted-by":"crossref","unstructured":"Chien CH, Chuang JY, Yang ST et al. (2019) Enrichment of superoxide dismutase 2 in glioblastoma confers to acquisition of temozolomide resistance that is associated with tumor-initiating cell subsets. J Biomed Sci 26:77. https:\/\/doi.org\/10.1186\/s12929-019-0565-2","DOI":"10.1186\/s12929-019-0565-2"},{"key":"2026072522431533278_j_aite-2026-0016_ref_018","doi-asserted-by":"crossref","unstructured":"Ding K, Liu C, Li L et al. (2023) Acyl-CoA synthase ACSL4: An essential target in ferroptosis and fatty acid metabolism. Chin Med J 136:2521\u20132537. https:\/\/doi.org\/10.1097\/cm9.0000000000002533","DOI":"10.1097\/CM9.0000000000002533"},{"key":"2026072522431533278_j_aite-2026-0016_ref_019","doi-asserted-by":"crossref","unstructured":"Endale HT, Tesfaye W, Mengstie TA (2023) ROS induced lipid peroxidation and their role in ferroptosis. Front Cell Dev Biol 11:1226044. https:\/\/doi.org\/10.3389\/fcell.2023.1226044","DOI":"10.3389\/fcell.2023.1226044"},{"key":"2026072522431533278_j_aite-2026-0016_ref_020","doi-asserted-by":"crossref","unstructured":"Feng H, Wang N, Zhang N et al. (2022) Alternative autophagy: Mechanisms and roles in different diseases. Cell Commun Signal 20:43. https:\/\/doi.org\/10.1186\/s12964-022-00851-1","DOI":"10.1186\/s12964-022-00851-1"},{"key":"2026072522431533278_j_aite-2026-0016_ref_021","doi-asserted-by":"crossref","unstructured":"Gao G, Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J Cell Biochem 80:53\u201372. https:\/\/doi.org\/10.1002\/1097-4644(20010101)80:1<53:aid-jcb60>3.0.co;2-e","DOI":"10.1002\/1097-4644(20010101)80:1<53::AID-JCB60>3.0.CO;2-E"},{"key":"2026072522431533278_j_aite-2026-0016_ref_022","doi-asserted-by":"crossref","unstructured":"Gharat SA, Momin M, Bhavsar C (2016) Oral squamous cell carcinoma: Current Treatment strategies and nanotechnology-based approaches for prevention and therapy. Crit Rev Ther Drug Carrier Syst 33:363\u2013400. https:\/\/doi.org\/10.1615\/CritRevTherDrugCarrierSyst.2016016272","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2016016272"},{"key":"2026072522431533278_j_aite-2026-0016_ref_023","doi-asserted-by":"crossref","unstructured":"Hashem S, Ali TA, Akhtar S et al. (2022) Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed Pharmacother 150:113054. https:\/\/doi.org\/10.1016\/j.biopha.2022.113054","DOI":"10.1016\/j.biopha.2022.113054"},{"key":"2026072522431533278_j_aite-2026-0016_ref_024","doi-asserted-by":"crossref","unstructured":"Huang CH, Huang TY, Chang WJ et al. (2020) Combined treatment of heteronemin and tetrac induces antiproliferation in oral cancer cells. Mar Drugs 18:348. https:\/\/doi.org\/10.3390\/md18070348","DOI":"10.3390\/md18070348"},{"key":"2026072522431533278_j_aite-2026-0016_ref_025","doi-asserted-by":"crossref","unstructured":"Hu F, Han J, Zhai B et al. (2014) Blocking autophagy enhances the apoptosis effect of bufalin on human hepatocellular carcinoma cells through endoplasmic reticulum stress and JNK activation. Apoptosis 19:210\u2013223. https:\/\/doi.org\/10.1007\/s10495-013-0914-7","DOI":"10.1007\/s10495-013-0914-7"},{"key":"2026072522431533278_j_aite-2026-0016_ref_026","doi-asserted-by":"crossref","unstructured":"Isoyama S, Tamaki N, Noguchi Y et al. (2023) Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors. Cell Death Dis 14:169. https:\/\/doi.org\/10.1038\/s41419-023-05690-7","DOI":"10.1038\/s41419-023-05690-7"},{"key":"2026072522431533278_j_aite-2026-0016_ref_027","doi-asserted-by":"crossref","unstructured":"Jelinek A, Heyder L, Daude M et al. (2018) Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic Biol Med 117:45\u201357. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2018.01.019","DOI":"10.1016\/j.freeradbiomed.2018.01.019"},{"key":"2026072522431533278_j_aite-2026-0016_ref_028","doi-asserted-by":"crossref","unstructured":"Jung CH, Kim EM, Song JY et al. (2019) Mitochondrial superoxide dismutase 2 mediates \u03b3-irradiation-induced cancer cell invasion. Exp Mol Med 51:1\u201310. https:\/\/doi.org\/10.1038\/s12276-019-0207-5","DOI":"10.1038\/s12276-019-0207-5"},{"key":"2026072522431533278_j_aite-2026-0016_ref_029","doi-asserted-by":"crossref","unstructured":"Lau CC, Aminuddin A, Chan KM et al. (2021) Extracellular ATP induced S-phase cell cycle arrest via p2y receptor-activated ERK signaling in poorly differentiated oral squamous cell carcinoma SAS cells. Life 11:1170. https:\/\/doi.org\/10.3390\/life11111170","DOI":"10.3390\/life11111170"},{"key":"2026072522431533278_j_aite-2026-0016_ref_030","doi-asserted-by":"crossref","unstructured":"Lee YS, Kalimuthu K, Park YS et al. (2020) BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis. Apoptosis 25:625\u2013631. https:\/\/doi.org\/10.1007\/s10495-020-01627-z","DOI":"10.1007\/s10495-020-01627-z"},{"key":"2026072522431533278_j_aite-2026-0016_ref_031","doi-asserted-by":"crossref","unstructured":"Lee MG, Liu YC, Lee YL et al. (2018) Heteronemin, a marine sesterterpenoid-type metabolite, induces apoptosis in prostate LNcap cells via oxidative and ER stress combined with the inhibition of topoisomerase II and Hsp90. Mar Drugs 16:204. https:\/\/doi.org\/10.3390\/md16060204","DOI":"10.3390\/md16060204"},{"key":"2026072522431533278_j_aite-2026-0016_ref_032","doi-asserted-by":"crossref","unstructured":"Li X, Wang TX, Huang X et al. (2020) Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity. Liver Int 40:1378\u20131394. https:\/\/doi.org\/10.1111\/liv.14428","DOI":"10.1111\/liv.14428"},{"key":"2026072522431533278_j_aite-2026-0016_ref_033","doi-asserted-by":"crossref","unstructured":"Li H, Zhang Y, Xu M et al. (2022) Current trends of targeted therapy for oral squamous cell carcinoma. J Cancer Res Clin Oncol 148:2169\u20132186. https:\/\/doi.org\/10.1007\/s00432-022-04028-8","DOI":"10.1007\/s00432-022-04028-8"},{"key":"2026072522431533278_j_aite-2026-0016_ref_034","doi-asserted-by":"crossref","unstructured":"Maciel M, Hern\u00e1ndez-Barrientos D, Herrera I et al. (2018) Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury. Aging 10:2098\u20132112. https:\/\/doi.org\/10.18632\/aging.101532","DOI":"10.18632\/aging.101532"},{"key":"2026072522431533278_j_aite-2026-0016_ref_035","doi-asserted-by":"crossref","unstructured":"Mahjour F, Dambal V, Shrestha N et al. (2019) Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: Synergy with PDGF-AB. Oncogenesis 8:34. https:\/\/doi.org\/10.1038\/s41389-019-0144-0","DOI":"10.1038\/s41389-019-0144-0"},{"key":"2026072522431533278_j_aite-2026-0016_ref_036","doi-asserted-by":"crossref","unstructured":"Masui A, Hamada M, Kameyama H et al. (2016) Autophagy as a survival mechanism for squamous cell carcinoma cells in endonuclease G-mediated apoptosis. PLoS One 11:e0162786. https:\/\/doi.org\/10.1371\/journal.pone.0162786","DOI":"10.1371\/journal.pone.0162786"},{"key":"2026072522431533278_j_aite-2026-0016_ref_037","doi-asserted-by":"crossref","unstructured":"Mollaei M, Hassan ZM, Khorshidi F et al. (2021) Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells? Transl Oncol 14:101056. https:\/\/doi.org\/10.1016\/j.tranon.2021.101056","DOI":"10.1016\/j.tranon.2021.101056"},{"key":"2026072522431533278_j_aite-2026-0016_ref_038","doi-asserted-by":"crossref","unstructured":"Mustafa AG, Alfaqih MA, Al-Shboul O (2018) The 4-hydroxynonenal mediated oxidative damage of blood proteins and lipids involves secondary lipid peroxidation reactions. Exp Ther Med 16:2132\u20132137. https:\/\/doi.org\/10.3892\/etm.2018.6419","DOI":"10.3892\/etm.2018.6419"},{"key":"2026072522431533278_j_aite-2026-0016_ref_039","doi-asserted-by":"crossref","unstructured":"Neophytou CM, Trougakos IP, Erin N et al. (2021) Apoptosis deregulation and the development of cancer multi-drug resistance. Cancers (Basel) 13:4363. https:\/\/doi.org\/10.3390\/cancers13174363","DOI":"10.3390\/cancers13174363"},{"key":"2026072522431533278_j_aite-2026-0016_ref_040","doi-asserted-by":"crossref","unstructured":"Ohnishi Y, Yasui H, Nozaki M et al. (2018) Molecularly-targeted therapy for the oral cancer stem cells. Jpn Dent Sci Rev 54:88\u2013103. https:\/\/doi.org\/10.1016\/j.jdsr.2017.11.001","DOI":"10.1016\/j.jdsr.2017.11.001"},{"key":"2026072522431533278_j_aite-2026-0016_ref_041","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a-Martinez C, Rickman AD, Heckmann BL (2022) Beyond autophagy: LC3-associated phagocytosis and endocytosis. Sci Adv 8:eabn1702. https:\/\/doi.org\/10.1126\/sciadv.abn1702","DOI":"10.1126\/sciadv.abn1702"},{"key":"2026072522431533278_j_aite-2026-0016_ref_042","doi-asserted-by":"crossref","unstructured":"Pigeolet E, Corbisier P, Houbion A et al. (1990) Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech Ageing Dev 51:283\u2013297. https:\/\/doi.org\/10.1016\/0047-6374(90)90078-t","DOI":"10.1016\/0047-6374(90)90078-T"},{"key":"2026072522431533278_j_aite-2026-0016_ref_043","doi-asserted-by":"crossref","unstructured":"Redza-Dutordoir M, Averill-Bates DA (2016) Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica Biophysica Acta 1863:2977\u20132992. https:\/\/doi.org\/10.1016\/j.bbamcr.2016.09.012","DOI":"10.1016\/j.bbamcr.2016.09.012"},{"key":"2026072522431533278_j_aite-2026-0016_ref_044","doi-asserted-by":"crossref","unstructured":"Rimondi E, Melloni E, Romani A et al. (2021) Overcoming of microenvironment protection on primary chronic lymphocytic leukemia cells after treatment with BTK and MDM2 pharmacological inhibitors. Curr Oncol 28:2439\u20132451. https:\/\/doi.org\/10.3390\/curroncol28040223","DOI":"10.3390\/curroncol28040223"},{"key":"2026072522431533278_j_aite-2026-0016_ref_045","doi-asserted-by":"crossref","unstructured":"Saelens X, Festjens N, Vande Walle L et al. (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23:2861\u20132874. https:\/\/doi.org\/10.1038\/sj.onc.1207523","DOI":"10.1038\/sj.onc.1207523"},{"key":"2026072522431533278_j_aite-2026-0016_ref_046","doi-asserted-by":"crossref","unstructured":"Seo Y, Lim H, Park H et al. (2023) Recent progress of lipid nanoparticles-based lipophilic drug delivery: Focus on surface modifications. Pharmaceutics 15:772. https:\/\/doi.org\/10.3390\/pharmaceutics15030772","DOI":"10.3390\/pharmaceutics15030772"},{"key":"2026072522431533278_j_aite-2026-0016_ref_047","doi-asserted-by":"crossref","unstructured":"Soond SM, Savvateeva LV, Makarov VA et al. (2021) Cathepsin S cleaves BAX as a novel and therapeutically important regulatory mechanism for apoptosis. Pharmaceutics 13:339. https:\/\/doi.org\/10.3390\/pharmaceutics13030339","DOI":"10.3390\/pharmaceutics13030339"},{"key":"2026072522431533278_j_aite-2026-0016_ref_048","doi-asserted-by":"crossref","unstructured":"Su LJ, Zhang JH, Gomez H et al. (2019) Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev 2019:5080843. https:\/\/doi.org\/10.1155\/2019\/5080843","DOI":"10.1155\/2019\/5080843"},{"key":"2026072522431533278_j_aite-2026-0016_ref_049","doi-asserted-by":"crossref","unstructured":"Thom\u00e9 MP, Filippi-Chiela EC, Villodre ES et al. (2016) Ratiometric analysis of Acridine Orange staining in the study of acidic organelles and autophagy. J Cell Sci 129:4622\u20134632. https:\/\/doi.org\/10.1242\/jcs.195057","DOI":"10.1242\/jcs.195057"},{"key":"2026072522431533278_j_aite-2026-0016_ref_050","doi-asserted-by":"crossref","unstructured":"Villalpando-Rodriguez GE, Gibson SB (2021) Reactive oxygen species (ROS) regulates different types of cell death by acting as a rheostat. Oxid Med Cell Longev 2021:912436. https:\/\/doi.org\/10.1155\/2021\/9912436","DOI":"10.1155\/2021\/9912436"},{"key":"2026072522431533278_j_aite-2026-0016_ref_051","doi-asserted-by":"crossref","unstructured":"Wang K, Chen YF, Yang YSH et al. (2022) The power of heteronemin in cancers. J Biomed Sci 29:41. https:\/\/doi.org\/10.1186\/s12929-022-00816-z","DOI":"10.1186\/s12929-022-00816-z"},{"key":"2026072522431533278_j_aite-2026-0016_ref_052","doi-asserted-by":"crossref","unstructured":"Weckx A, Riekert M, Grandoch A et al. (2019) Time to recurrence and patient survival in recurrent oral squamous cell carcinoma. Oral Oncol 94:8\u201313. https:\/\/doi.org\/10.1016\/j.oraloncology.2019.05.002","DOI":"10.1016\/j.oraloncology.2019.05.002"},{"key":"2026072522431533278_j_aite-2026-0016_ref_053","unstructured":"Weydert C, Roling B, Liu J et al. (2003) Suppression of the malignant phenotype in human pancreatic cancer cells by the overexpression of manganese superoxide dismutase. Mol Cancer Ther 2:361\u2013369."},{"key":"2026072522431533278_j_aite-2026-0016_ref_054","doi-asserted-by":"crossref","unstructured":"Wilar G, Suhandi C, Wathoni N et al. (2024) Nanoparticle-based drug delivery systems enhance treatment of cognitive defects. Int J Nanomedicine 19:11357\u201311378. https:\/\/doi.org\/10.2147\/ijn.S484838","DOI":"10.2147\/IJN.S484838"},{"key":"2026072522431533278_j_aite-2026-0016_ref_055","doi-asserted-by":"crossref","unstructured":"Wongchitrat P, Samutpong A, Lerdsamran H et al. (2019) Elevation of cleaved p18 bax levels associated with the kinetics of neuronal cell death during Japanese encephalitis virus infection. Int J Mol Sci 20:5016. https:\/\/doi.org\/10.3390\/ijms20205016","DOI":"10.3390\/ijms20205016"},{"key":"2026072522431533278_j_aite-2026-0016_ref_056","doi-asserted-by":"crossref","unstructured":"Wood DE, Newcomb EW (2000) Cleavage of Bax enhances its cell death function. Exp Cell Res 256:375\u2013382. https:\/\/doi.org\/10.1006\/excr.2000.4859","DOI":"10.1006\/excr.2000.4859"},{"key":"2026072522431533278_j_aite-2026-0016_ref_057","doi-asserted-by":"crossref","unstructured":"Wu SY, Sung PJ, Chang YL et al. (2015) Heteronemin, a Spongean sesterterpene, induces cell apoptosis and autophagy in human renal carcinoma cells. Biomed Res Int 2015:738241. https:\/\/doi.org\/10.1155\/2015\/738241","DOI":"10.1155\/2015\/738241"},{"key":"2026072522431533278_j_aite-2026-0016_ref_058","doi-asserted-by":"crossref","unstructured":"Wu JC, Wang CT, Hung HC et al. (2016) Heteronemin is a novel c-Met\/STAT3 inhibitor against advanced prostate cancer cells. Prostate 76:1469\u20131483. https:\/\/doi.org\/10.1002\/pros.23230","DOI":"10.1002\/pros.23230"},{"key":"2026072522431533278_j_aite-2026-0016_ref_059","doi-asserted-by":"crossref","unstructured":"Wu TT, Zhou SH (2015) Nanoparticle-based targeted therapeutics in head-and-neck cancer. Int J Med Sci 12:187\u2013200. https:\/\/doi.org\/10.7150\/ijms.10083","DOI":"10.7150\/ijms.10083"},{"key":"2026072522431533278_j_aite-2026-0016_ref_060","doi-asserted-by":"crossref","unstructured":"Xiao M, Benoit A, Hasmim M et al. (2021) Targeting cytoprotective autophagy to enhance anticancer therapies. Front Oncol 11:626309. https:\/\/doi.org\/10.3389\/fonc.2021.626309","DOI":"10.3389\/fonc.2021.626309"},{"key":"2026072522431533278_j_aite-2026-0016_ref_061","doi-asserted-by":"crossref","unstructured":"Yan HF, Zou T, Tuo QZ et al. (2021) Ferroptosis: Mechanisms and links with diseases. Signal Transduct Target Ther 6:49. https:\/\/doi.org\/10.1038\/s41392-020-00428-9","DOI":"10.1038\/s41392-020-00428-9"},{"key":"2026072522431533278_j_aite-2026-0016_ref_062","doi-asserted-by":"crossref","unstructured":"Ye J, Zhang R, Wu F et al. (2018) Non-apoptotic cell death in malignant tumor cells and natural compounds. Cancer Lett 420:210\u2013227. https:\/\/doi.org\/10.1016\/j.canlet.2018.01.061","DOI":"10.1016\/j.canlet.2018.01.061"},{"key":"2026072522431533278_j_aite-2026-0016_ref_063","doi-asserted-by":"crossref","unstructured":"Yin H, Xu L, Porter NA (2011) Free radical lipid peroxidation: Mechanisms and analysis. Chem Rev 111:5944\u20135972. https:\/\/doi.org\/10.1021\/cr200084z","DOI":"10.1021\/cr200084z"},{"key":"2026072522431533278_j_aite-2026-0016_ref_064","doi-asserted-by":"crossref","unstructured":"Yu J, Yao T, Zhang M et al. (2025) Correlations of phosphorylated Nrf2 with responses to neoadjuvant chemotherapy in patients with triple-negative breast cancer. BMC Womens Health 25:347. https:\/\/doi.org\/10.1186\/s12905-025-03896-9","DOI":"10.1186\/s12905-025-03896-9"},{"key":"2026072522431533278_j_aite-2026-0016_ref_065","doi-asserted-by":"crossref","unstructured":"Zada S, Hwang JS, Ahmed M et al. (2021) Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy. Biochim Biophys Acta Rev Cancer 187:188565. https:\/\/doi.org\/10.1016\/j.bbcan.2021.188565","DOI":"10.1016\/j.bbcan.2021.188565"},{"key":"2026072522431533278_j_aite-2026-0016_ref_066","doi-asserted-by":"crossref","unstructured":"Zhai X, Lin Y, Zhu L et al. (2024) Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications. Cytokine Growth Factor Rev 75:101\u2013109. https:\/\/doi.org\/10.1016\/j.cytogfr.2023.08.004","DOI":"10.1016\/j.cytogfr.2023.08.004"},{"key":"2026072522431533278_j_aite-2026-0016_ref_067","doi-asserted-by":"crossref","unstructured":"Zhang M, Liang J, Yang Y et al. (2020a) Current trends of targeted drug delivery for oral cancer therapy. Front Bioeng Biotechnol 8:618931. https:\/\/doi.org\/10.3389\/fbioe.2020.618931","DOI":"10.3389\/fbioe.2020.618931"},{"key":"2026072522431533278_j_aite-2026-0016_ref_068","doi-asserted-by":"crossref","unstructured":"Zhang C, Liu X, Jin S et al. (2022) Ferroptosis in cancer therapy: A novel approach to reversing drug resistance. Mol Cancer 21:47. https:\/\/doi.org\/10.1186\/s12943-022-01530-y","DOI":"10.1186\/s12943-022-01530-y"},{"key":"2026072522431533278_j_aite-2026-0016_ref_069","doi-asserted-by":"crossref","unstructured":"Zhang X, Sui S, Wang L et al. (2020b) Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J Cell Physiol 235:3425\u20133437. https:\/\/doi.org\/10.1002\/jcp.29232","DOI":"10.1002\/jcp.29232"},{"key":"2026072522431533278_j_aite-2026-0016_ref_070","doi-asserted-by":"crossref","unstructured":"Zhong H, Yin H (2015) Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol 4:193\u2013199. https:\/\/doi.org\/10.1016\/j.redox.2014.12.011","DOI":"10.1016\/j.redox.2014.12.011"}],"container-title":["Archivum Immunologiae et Therapiae Experimentalis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/reference-global.com\/pdf\/10.2478\/aite-2026-0016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T22:43:38Z","timestamp":1785019418000},"score":1,"resource":{"primary":{"URL":"https:\/\/reference-global.com\/article\/10.2478\/aite-2026-0016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,7,4]]},"published-print":{"date-parts":[[2026,1,1]]}},"alternative-id":["10.2478\/aite-2026-0016"],"URL":"https:\/\/doi.org\/10.2478\/aite-2026-0016","relation":{},"ISSN":["1661-4917"],"issn-type":[{"value":"1661-4917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,1]]},"article-number":"20260016"}}