Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.

Genetic heterogeneity contributes to the variable therapeutic responses in cancers. Frequent SPOP mutations and recurrent CHD1 deletions define distinct molecular subtypes of prostate cancer (PCa) with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify SPOP mutations and CHD1 deletion as key genetic determinants of ferroptosis susceptibility in PCa. Using genetically engineered human and murine models, we show that SPOP mutations enhance, whereas CHD1 deletion impairs, the efficacy of ferroptosis inducers targeting GPX4. Mechanistically, SPOP and CHD1 exert opposing effects on ferroptosis by antagonistically regulating the MYC-ACSL4 axis. Furthermore, we demonstrate that targeting cholesterol metabolism with cholesterol-lowering agents restores ACSL4 expression and re-sensitizes SPOP/CHD1 co-deficient tumors to ferroptosis-inducing therapy. Our findings establish SPOP/CHD1 as upstream genetic regulators of ferroptosis and provide biomarker-driven combinatorial strategies to enhance ferroptosis-based therapy in men with advanced PCa.