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Aims <p>Resistance to enzalutamide (Enza) in castration-resistant prostate cancer (CRPC) is linked to poor prognosis. While KDM5B is highly expressed in Enza-resistant CRPC, the mechanisms of resistance remain poorly understood.</p> Methods <p>We applied an integrated approach to study KDM5B using bioinformatics analyses of single-cell and multi-omics data, along with in vitro and in vivo validation. We explored mechanisms through lactylation proteomics, CRISPR/Cas9 editing, ChIP, and dual-luciferase reporter assays.</p> Results <p>KDM5B induces Enza resistance by epigenetically suppressing PTEN, which in turn activates the PI3K/Akt signaling pathway to upregulate PGK1 and drive metabolic reprogramming and lactate production. Lactate acts as a substrate for p300-mediated lactylation of hnRNPA1 at lysine 179 (K179), stabilizing hnRNPA1 by blocking NEDD4L-mediated ubiquitination and promoting AR-V7 splicing. A potential positive feedback loop enhances this effect: KDM5B activates AR, and AR, in turn, increases KDM5B expression. Inhibiting KDM5B or p300 can reverse Enza resistance in vivo.</p> Conclusions <p>We identify a mechanism linking metabolism, epigenetics, and a KDM5B/AR feedback loop in drug resistance. These findings suggest that multi-target strategies may represent a promising approach to overcome Enza resistance in CRPC.</p>

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KDM5B-driven glucose metabolic reprogramming promotes enzalutamide resistance in prostate cancer via the lactate/hnRNPA1 lactylation/AR-V7 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Rui Sun,
  • Yong Huang,
  • Hao He,
  • Qiuchen Li,
  • Linfeng Wang,
  • Gaojie Zhang,
  • Ziling Wei,
  • Yang Cao,
  • Jing Li,
  • Xianmin Wang,
  • Fan Yang,
  • Wenjun Chen,
  • Xiang Li,
  • Jiang Yu,
  • Siyuan Liu,
  • Congfeng Lei,
  • Yu Jiang,
  • Yueqiang Peng,
  • Huiyi Su,
  • Yingying Gao,
  • Weiyang He,
  • Lei Yang,
  • Jiayu Liu

摘要

Aims

Resistance to enzalutamide (Enza) in castration-resistant prostate cancer (CRPC) is linked to poor prognosis. While KDM5B is highly expressed in Enza-resistant CRPC, the mechanisms of resistance remain poorly understood.

Methods

We applied an integrated approach to study KDM5B using bioinformatics analyses of single-cell and multi-omics data, along with in vitro and in vivo validation. We explored mechanisms through lactylation proteomics, CRISPR/Cas9 editing, ChIP, and dual-luciferase reporter assays.

Results

KDM5B induces Enza resistance by epigenetically suppressing PTEN, which in turn activates the PI3K/Akt signaling pathway to upregulate PGK1 and drive metabolic reprogramming and lactate production. Lactate acts as a substrate for p300-mediated lactylation of hnRNPA1 at lysine 179 (K179), stabilizing hnRNPA1 by blocking NEDD4L-mediated ubiquitination and promoting AR-V7 splicing. A potential positive feedback loop enhances this effect: KDM5B activates AR, and AR, in turn, increases KDM5B expression. Inhibiting KDM5B or p300 can reverse Enza resistance in vivo.

Conclusions

We identify a mechanism linking metabolism, epigenetics, and a KDM5B/AR feedback loop in drug resistance. These findings suggest that multi-target strategies may represent a promising approach to overcome Enza resistance in CRPC.