Spatial Metabolic Modeling Reveals Zinc–Citrate Rewiring and Therapeutic Vulnerabilities in Prostate Cancer

Prostate cancer exhibits a metabolic phenotype distinct from the Warburg paradigm, characterized by reprogramming of the zinc-citrate secretory axis that normally drives citrate accumulation and secretion in prostatic epithelium. How this metabolic rewiring is organized across the spatial architecture of tumors and linked to androgen receptor (AR) signaling remains poorly understood. We integrated spatial transcriptomics data from twelve regions spanning normal, inflamed, and Gleason-graded prostate tissues with genome-scale metabolic modeling to quantify metabolic activity across tissue states. The analysis identified the zinc-citrate-aconitase axis as a central feature of prostate cancer metabolic reprogramming, linking increased aconitase activity to enhanced citrate export, acetyl-CoA generation, and de novo lipogenesis. Metabolic similarity was more strongly associated with spatial proximity than with histological classification, suggesting field-level metabolic reprogramming beyond visible pathological boundaries. AR activity displayed grade-dependent associations with lipid metabolic pathways, indicating heterogeneous coupling between androgen signaling and metabolism across tumor regions. Consistent with the established biology of prostate cancer, predicted flux distributions did not support a classical Warburg phenotype. A flux-based target prioritization framework identified HMGCR, FASN, and SLC25A1 as candidate therapeutic targets, with independent support from TCGA-PRAD expression profiles and DepMap CRISPR essentiality data. Together, these findings provide a spatially resolved view of prostate cancer metabolism, establish the zinc-citrate axis as a dominant feature of metabolic organization, and identify candidate metabolic vulnerabilities for therapeutic intervention.