Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells

Abstract

Ovarian cancer (OVCA) is a highly malignant gynecological tumor characterized by a dismal 5-year survival rate that is closely linked to aberrant ferroptosis regulation and lipid metabolic reprogramming. This study integrated bioinformatics analyses of TCGA and The Human Protein Atlas datasets, clinical validation in 30 pairs of OVCA tissues, in vitro functional assays using HO8910 and HEYT30 cell lines, and nude mouse xenograft models to explore the role of suppressor of cytokine signaling 6 (SOCS6) in OVCA prognosis. The results revealed that SOCS6 was significantly downregulated in OVCA tissues and cell lines, and low expression was strongly correlated with poor patient prognosis. Mechanistically, SOCS6 overexpression inhibited cellular proliferation, migration, and invasion and enhanced sensitivity to the ferroptosis inducer erastin. This effect occurs by promoting the ubiquitin-proteasomal degradation of the ferroptosis antagonist SLC7A11, reducing intracellular glutathione (GSH) levels, and augmenting reactive oxygen species (ROS) and Fe²⁺ accumulation. Additionally, SOCS6 suppressed de novo fatty acid synthesis by downregulating the key enzymes FASN and ACC, leading to decreased triglyceride and phospholipid production. In vivo xenograft experiments confirmed that SOCS6 overexpression inhibited tumor growth and reduced the expression of SLC7A11 and lipid metabolism-related molecules. Collectively, these results establish SOCS6 as a critical molecular hub linking ferroptosis and lipid metabolism in OVCA, highlighting its potential as both a prognostic biomarker and a therapeutic target for improving clinical outcomes in OVCA.