CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors.

Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC.