SPOP和CHD1在ACSL4调控中的分歧作用揭示了前列腺癌中靶向铁死亡的情境依赖性易感性

Background: Genetic heterogeneity fundamentally shapes therapeutic responses in prostate cancer (PCa). Among the most recurrent alterations, SPOP mutations and CHD1 loss define molecularly distinct PCa subtypes that respond differently to androgen signaling-directed therapies. Ferroptosis, an iron-dependent form of cell death driven by unchecked lipid peroxidation, has recently emerged as a promising therapeutic vulnerability; however, the genetic determinants that govern ferroptosis responsiveness in PCa remain poorly defined. Methods: We integrated engineered human cell lines, 3D organoid systems, genetically engineered mouse models (GEMMs) and isogenic xenografts to dissect how SPOP mutation and CHD1 deletion modulate ferroptotic sensitivity. Ferroptosis induction and GPX4 dependence were assessed using pharmacologic GPX4 inhibitors (RSL3, ML162, and JKE1674), lipid peroxidation assays, and ferroptosis rescue controls. Transcriptomic, lipidomic, and biochemical analyses, together with ChIP-seq, ChIP-qPCR, and ACSL4 promoter-luciferase reporter assays, were used to delineate how SPOP mutations and CHD1 deletion modulate the MYC-ACSL4 transcriptional axis. Results: We uncover opposing roles for SPOP and CHD1 in regulating ferroptosis. SPOP mutations markedly sensitize PCa cells and tumors to GPX4 inhibition, whereas CHD1 loss abrogates this vulnerability and confers ferroptosis resistance. Mechanistically, SPOP mutation enhances, while CHD1 deletion suppresses, activation of the MYC-ACSL4 axis. SPOP mutation promotes, and CHD1 loss diminishes, MYC occupancy and transcriptional activation of ACSL4, a key enzyme governing polyunsaturated fatty acid metabolism and ferroptotic lipid peroxidation. Given our prior discovery that CHD1 loss upregulates cholesterol biosynthesis, we asked whether inhibiting this pathway could reverse ferroptosis resistance. Notably, pharmacologic blockade of cholesterol biosynthesis reinstates ACSL4 expression and restores ferroptosis sensitivity in SPOP-mutant/CHD1-deficient tumors in vivo, identifying a targetable metabolic checkpoint underlying ferroptosis resistance. Conclusions: These findings define SPOP mutation and CHD1 loss as antagonistic genetic determinants of ferroptosis and uncover a MYC-ACSL4-dependent mechanism that governs GPX4 reliance. Pharmacologic inhibition of cholesterol biosynthesis overcomes CHD1-driven ferroptosis resistance, enabling a biomarker-guided combination strategy that couples ferroptosis induction with cholesterol-pathway blockade. This work establishes a precision strategy for exploiting ferroptosis-based combination therapies in genetically stratified PCa.