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

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 PTEN, which in turn transcriptionally up-regulating PGK1. • Lactate causes lactylation of lysine at position 179 of hnRNPA1, leading to abnormal splicing of AR and upregulation of AR-V7. • p300/HDAC1/HDAC2 jointly regulate the lactylation process of hnRNPA1. • The ligand-independent AR signaling pathway positively feedback promotes the upregulation of KDM5B expression.