Silencing myeloid cell leukemia-1 improves apoptotic and ferroptotic responses in melanoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41540498", "kind": "science-record", "revision": 4, "content_hash": "sha256:55959d6307b2ea33f001fe7db13e74aaef0c2d2e89f9063229d9e45c48419a2d", "created_at": "2026-11-01T20:31:30Z", "updated_at": "2026-11-01T22:57:44Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Silencing myeloid cell leukemia-1 improves apoptotic and ferroptotic responses in melanoma.", "doi": "10.1186/s40001-026-03833-y", "pmid": "41540498", "authors": ["Fang Fang", "Qiuyun Xu", "Shuyi Shen", "Songyu Wang", "Chengbei Bao"], "journal": "European journal of medical research", "year": 2026, "abstract": "BACKGROUND: Melanoma is a highly malignant skin cancer characterized by strong metastatic and invasive capabilities. Integrative transcriptomic profiling offers a systematic route to uncover tumor-specific regulatory hubs that could expose new therapeutic vulnerabilities. By combining multi-cohort bioinformatics screening with mechanistic cell-based assays, we sought to delineate critical drivers of disease progression in melanoma.\nMETHODS: An integrative analysis of three GEO microarray cohorts (GSE3189, GSE46517, GSE114445) identified hub genes through differential-expression filtering, protein-protein interaction mapping, and CytoHubba ranking. MCL1 was prioritized as the top network hub, prompting its selection for functional validation. B16F1 murine melanoma cells were transfected with MCL1-specific siRNA or a non-targeting control. Cell viability (CCK-8), scratch-wound migration, adhesion, Annexin V/PI apoptosis, cell-cycle distribution, and reactive-oxygen species (ROS) were quantified. Western blots probed apoptosis, cell cycle, and ferroptosis-related proteins; glutathione (GSH) and malondialdehyde (MDA) were measured by ELISA; mitochondrial ultrastructure was examined by transmission electron microscopy. Ferrostatin-1 (Fer-1) was used to assess the functional relevance of ferroptosis.\nRESULTS: In silico analysis prioritized MCL1 as the top hub within a 136-gene melanoma consensus signature. siRNA achieved > 80% knock-down of Mcl-1 mRNA and protein in B16F1 cells, resulting in: (i) significant reductions in cell viability, migration, and adhesion; (ii) substantial elevation of apoptosis with upregulating Bax, downregulating Bcl-2 and caspase-9/3 activation; (iii) G1-phase arrest accompanied by p53/p21 upregulation; and (iv) a ferroptotic phenotype typified by GSH depletion, MDA/ROS accumulation, mitochondrial swelling, reduced GPX4/SLC7A11 ratio, and higher ACSL4/NCOA4 ratio. Fer-1 partially rescued these molecular alterations yet did not fully restore growth, indicating that Mcl-1 coordinates both caspase-dependent apoptosis and lipid peroxidation-driven ferroptosis in melanoma.\nCONCLUSIONS: Overall, our findings pinpoint that Mcl-1 operates as a multifaceted survival node in melanoma, concurrently sustaining proliferation, migration, and redox homeostasis while suppressing apoptotic and ferroptotic death programs. Dual targeting of Mcl-1 and the ferroptosis pathway may offer a robust therapeutic strategy against melanoma.", "claims": [{"id": "claim-method", "statement": "Two-group comparisons used unpaired Student’s t-tests. For experiments with more than two groups, one-way ANOVA followed by Bonferroni post hoc correction was applied.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41540498", "locator": "sections[13] \"Statistical analysis\" paragraph 2", "quote": "Two-group comparisons used unpaired Student’s t-tests. For experiments with more than two groups, one-way ANOVA followed by Bonferroni post hoc correction was applied."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data is available from the corresponding author upon reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41540498", "locator": "sections[24] \"Data availability\" paragraph 2", "quote": "All data is available from the corresponding author upon reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The integrative screen identified MCL1 as the highest-scoring hub among 136 consensus differentially expressed genes shared by three melanoma cohorts.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41540498", "locator": "sections[15] \"Transcriptomic screening highlights MCL1 as a dominant regulatory node in melanoma\" paragraph 2", "quote": "Intersecting the three DEG lists distilled the signature to 136 genes common to all datasets (Fig. 2A)."}, {"asset": "source:pmid:41540498", "locator": "sections[15] \"Transcriptomic screening highlights MCL1 as a dominant regulatory node in melanoma\" paragraph 2", "quote": "The resulting PPI network highlighted MCL1 as the highest-scoring hub within a cluster of 13 top-degree nodes, which also included other BCL-2 family members (Fig. 2C)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The integrative screen identified MCL1 as the highest-scoring hub among 136 consensus differentially expressed genes shared by three melanoma cohorts.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:41540498"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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