JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer

Abstract Ferroptosis inducers have shown therapeutic potential in prostate cancer, but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic cross-talk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. In this study, we found that aberrant accumulation of Jumonji domain–containing 6 (JMJD6) proteins correlated with poorer prognosis of patients with prostate cancer. Mechanistically, prostate cancer–associated speckle-type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer–promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6–ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated prostate cancer selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple preclinical prostate cancer models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated prostate cancer to increase sensitivity to ferroptosis inducers. Significance: Elevated JMJD6 induced by mutant SPOP alters the epigenetic landscape to increase glutathione biosynthesis and protect prostate cancer cells from ferroptosis, highlighting the therapeutic potential of combining JMJD6 inhibitors and ferroptosis inducers.