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

作者：Rui Sun, Yong Huang, Hao He, Qiuchen Li, Linfeng Wang, Gaojie Zhang, Ziling Wei, Yang Cao, Jie Li, Xianmin Wang, Fan Yang, Wenjun Chen, Xiang Li, Jiang Yu, S. Liu, Congfeng Lei, Yu Jiang, y. peng, Huiyi Su, Yingying Gao, Weiyang He, Lei Yang, Jiayi Liu · 发表于：Molecular Cancer · 年份：2026 · DOI：10.1186/s12943-026-02602-z · 被引用次数：4 · 研究领域：Prostate Cancer Treatment and Research、Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis

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. 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. 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. 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. • KDM5B is a histone demethylase that is upregulated in enzalutamide resistant prostate cancer. • KDM5B drives tumor metabolic reprogramming by activating PI3K/Akt pathway through epigenetic inhibition of...