2026-10-07T02:15:44Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33667438 2026-09-12T12:47:54Z category_24778 category_24808 category_24790 category_24787 item_type_3 month_year_09_2026

SC-2001 triggers ferroptosis in glioblastoma by STAT3 inhibition-mediated ACSL4 derepression and lipid remodeling Xinyi Zhang (24833216) Qian Sun (24833335) Yuxin Wei (24833341) Xiaodian He (24833354) Shangwen Yang (24833367) Baohui Liu (24833374) Qianxue Chen (24763093) Cancer cell biology Solid tumours Chemotherapy Cancer therapy (excl. chemotherapy and radiation therapy) Glioblastoma SC-2001 Ferroptosis STAT3 ACSL4 Lipid peroxidation Background: Glioblastoma (GBM) remains incurable with profound therapeutic resistance. Ferroptosis offers a promising strategy, yet its regulatory mechanisms in GBM are incompletely defined.Methods: We evaluated SC‑2001, a STAT3 inhibitor, in GBM cell lines (U251, U-87 MG) and a xenograft model. Ferroptosis was assessed by GSH, ROS, lipid ROS, MDA, and mitochondrial morphology. STAT3/ACSL4 axis was examined via immunoblotting, qRT‑PCR, luciferase reporter assays, and gas chromatography-mass spectrometry (GC-MS) analysis of fatty acids. STAT3 overexpression and ACSL4 knockdown were used for mechanistic validation.Results: SC-2001 suppressed proliferation, migration, and invasion and induced GSH depletion, lipid peroxidation, and mitochondrial changes consistent with ferroptosis. Ferrostatin-1 partially rescued the loss of viability, whereas apoptosis and necroptosis inhibitors did not under the tested conditions. SC-2001 reduced nuclear p-STAT3, increased ACSL4 mRNA and protein levels and ACSL4 promoter activity, and upregulated FADS2 and LPCAT3. GC-MS revealed increased PUFA and decreased MUFA levels. In SC-2001-treated cells, arachidonic acid supplementation was associated with lower viability and higher MDA levels, whereas oleic acid had the opposite effects. STAT3 overexpression or ACSL4 knockdown attenuated the ferroptosis-associated phenotypes, supporting involvement of a STAT3-ACSL4 regulatory axis. In vivo, SC-2001 suppressed xenograft growth, reduced p-STAT3 and Ki-67 staining, and increased ACSL4, FADS2, and LPCAT3 expression.Conclusion: Our findings support a model in which SC-2001-induced inhibition of STAT3 signaling derepresses ACSL4 expression and contributes to altered fatty acid composition, lipid peroxidation, and ferroptosis in GBM cells. These results provide a preclinical rationale for further investigation of the STAT3-ACSL4 axis as a therapeutic target. 2026-09-12T12:47:54Z Dataset Dataset 10.6084/m9.figshare.33667438.v1 https://figshare.com/articles/dataset/_b_SC-2001_triggers_ferroptosis_in_glioblastoma_by_STAT3_inhibition-mediated_ACSL4_derepression_and_lipid_remodeling_b_/33667438 CC BY 4.0