<b>SC-2001 triggers ferroptosis in glioblastoma by STAT3 inhibition-mediated ACSL4 derepression and lipid remodeling</b>

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.</p><p dir="ltr"><b>Conclusion:</b> 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.</p>