The novel selective HDAC1 inhibitor ZJH-1 exhibits potent antitumor activity in castration-resistant prostate cancer, potentially involving HSP90AA1

= 65 nM in PC3 cells and 345 nM in patient-derived xenograft organoids (PDXOs)) via dual mechanisms: 1) cell cycle modulation, inducing G1 arrest through Cyclin D1 downregulation; and 2) intrinsic apoptosis induction, evidenced by caspase-3 cleavage and an elevated Bax/Bcl-2 ratio. ZJH-1 also showed potential to affect metastasis-related processes, as suggested by reduced activity of MMP-2/MMP-9 and reversed markers of epithelial-mesenchymal transition (EMT). Network pharmacology analysis predicted HSP90AA1 as a potential docking target of ZJH-1. Furthermore, protein expression analysis demonstrated that ZJH-1 upregulates disabled homolog 2 interacting protein (DAB2IP) and downregulates heat shock protein 90AA1 (HSP90AA1). In vivo, ZJH-1 (20 mg/kg, i.p.) significantly attenuated tumor growth in PC3 xenograft models (75 % volume reduction vs. controls) with no obvious weight loss or overt toxic side effects observed. These findings suggest that ZJH-1, a selective HDAC1 inhibitor, merits further investigation as a potential treatment for PCa.