HAAO‑derived quinolinic acid fuels FDPS‑dependent AR signaling and sensitizes prostate cancer to combination therapy.

Abstract

Emerging evidence highlights that metabolic reprogramming profoundly shapes the tumor microenvironment and immune evasion in prostate cancer. However, the functional role and mechanisms of tryptophan metabolism in prostate cancer progression remain unclear. Through single-cell transcriptomic analysis, we identified one tumor cell subtype characterized by high expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) and enhanced kynurenine pathway activity. This subpopulation leads to the accumulation of quinolinic acid (QA), a metabolic intermediate that could activate the mevalonate (MVA) pathway. Mechanistically, QA directly binds to and stabilizes farnesyl diphosphate synthase (FDPS), a key MVA pathway enzyme, thereby enhancing cholesterol biosynthesis and fueling androgen receptor (AR)-driven transcriptional programs. This HAAO/QA-FDPS axis establishes a metabolic crosstalk that links tryptophan catabolism to lipid metabolism, sustaining prostate tumor progression. Furthermore, an integrated prognostic model incorporating this pathway signatures outperforms other clinical variables alone, and HAAO-high tumors exhibit heightened sensitivity to combined inhibition of the kynurenine and AR pathways. Our study unveils a novel metabolic vulnerability in prostate cancer and provides a mechanistic rationale for targeting the HAAO/QA-FDPS axis for therapy.