{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T10:49:28Z","timestamp":1776941368561,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"South Africa\u2019s National Research Foundation","doi-asserted-by":"publisher","award":["MND210524603403"],"award-info":[{"award-number":["MND210524603403"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroblastoma is characterized by noticeable resistance to chemotherapy, largely driven by the ability of tumour cells to reorganize stress-adaptive signalling networks rather than relying on single oncogenic drivers. We conducted a study to investigate the pharmacological mode of action of doxorubicin in modifying adaptive signalling pathways in SH-SY5Y neuroblastoma cells, and whether the capacity of plant metabolites can exploit emergent biochemical vulnerabilities. Transcriptomic profiling through RNA sequencing conducted 48 h post-doxorubicin exposure unveiled the organized disruption of pathways linked with amyloidogenic processes, oncogenic signalling pathways, oxidative stress, and DNA repair. The protein\u2013protein interactions, coupled with Kyoto Encyclopedia of Genes and Genomes pathway evaluations, revealed five network-central-hubs: BRAF, GSK3\u03b2, PARP1, BACE1, and MAOB. Structural docking integrated with 200 ns molecular dynamics simulations illustrated binding stability across multiple targets driven by three metabolites, Lactol binding to BRAF (\u221254.13 kcal\/mol) and MAOB (\u221239.08 kcal\/mol), Amino(1H-indol-2-yl)acetic acid to BACE1 (\u221241.07 kcal\/mol) and GSK3\u03b2 (\u221247.38 kcal\/mol), and Quercetin-3-(6\u2033-malonyl-glucoside) binding to PARP1 (\u221246.03 kcal\/mol). In vitro Cell Counting Kit-8 proliferation assays validated the significant anti-neuroblastoma efficacy, with the lowest IC50 (0.2397 \u00b5M) being exhibited by Amino(1H-indol-2-yl)acetic acid, followed by Lactol (1.226 \u00b5M) and Quercetin-3-(6\u2033-malonyl-glucoside) (1.301 \u00b5M), which mirrored the cytotoxic action of doxorubicin (1.306 \u00b5M). These results suggest that plant-derived metabolites may interact with stress-adaptive signalling pathways connected with neuroblastoma. However, direct experimental validation of target engagement and pathway modulation will be required to confirm these predicted interactions.<\/jats:p>","DOI":"10.3390\/ijms27093739","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T10:10:17Z","timestamp":1776939017000},"page":"3739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network-Guided Identification of Plant-Derived Modulators of Stress-Adaptive Signalling in Neuroblastoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Mmei Cheryl","family":"Motshudi","sequence":"first","affiliation":[{"name":"Department of Biology, School of Science and Technology, Sefako Makgatho Health Science University, Pretoria 0204, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9164-8213","authenticated-orcid":false,"given":"Clarissa Marcelle","family":"Naidoo","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Science and Technology, Sefako Makgatho Health Science University, Pretoria 0204, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikwelu Lawrence","family":"Obi","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Science and Technology, Sefako Makgatho Health Science University, Pretoria 0204, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benson Chucks","family":"Iweriebor","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Science and Technology, Sefako Makgatho Health Science University, Pretoria 0204, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3048-4304","authenticated-orcid":false,"given":"Earl","family":"Prinsloo","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Rhodes University, Makhanda 6140, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Sulaiman","family":"Zubair","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Tadulako, Palu 94118, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3631-4522","authenticated-orcid":false,"given":"Nqobile Monate","family":"Mkolo","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Science and Technology, Sefako Makgatho Health Science University, Pretoria 0204, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhou, X., Wang, X., Li, N., Guo, Y., Yang, X., and Lei, Y. 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