JARID1D-dependent androgen receptor and JunD signaling activation of osteoclast differentiation inhibits prostate cancer bone metastasis through demethylating H3K4

<b>Rationale:</b> Bone metastasis and skeletal-related complications are primary causes of mortality in advanced-stage prostate cancer (PCa). Epigenetic regulation, particularly histone modification, plays a key role in this process; however, the underlying mechanisms remain elusive. <b>Methods and Results:</b> In mouse models, JARID1D was an important mediator of both visceral and bone metastases. Chromatin immunoprecipitation (ChIP) and immunofluorescence (IF) techniques showed that the H3K4me3 demethylation activity of JARID1D is a key factor in the dynamic regulation of androgen receptor (AR) expression. Further analysis using western blotting and bone culture systems indicated that knocking down JARID1D enhanced the expression of monoamine oxidase A (MAOA) through the AR signaling pathway, leading to increased secretion of the nuclear factor kappa B (NF-κB) ligand receptor activator (RANKL) by PCa cells. This in turn promotes osteoclast differentiation and facilitates bone metastasis. In addition, single-cell sequencing results indicated that a reduction in JARID1D levels directly affected osteoclasts, stimulated JunD transcription, and accelerated PCa bone metastasis progression. Finally, both <i>in vivo</i> and <i>in vitro</i> experiments confirmed that the JARID1D agonist JIB-04 effectively blocked these molecular pathways, thereby delaying the onset of bone metastasis in PCa. <b>Conclusions:</b> These insights provide a theoretical foundation for targeting JARID1D and related molecules in the treatment of PCa bone metastasis.