Background: Cyclin‐dependent kinase 12 (CDK12)‐deficient prostate cancer defines a subtype of castration‐resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive.Methods: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR‐Cas9 technology and mass spectrometry‐based metabolomic profiling to reveal the metabolic characteristics of CDK12‐deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency‐mediated CRPC metabolic reprogramming, we utilized cell RNA‐seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP‐qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS‐010759 on CDK12‐deficient CRPC.Results: CDK12‐deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12‐deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12‐deficient prostate cancer.Conclusions: Our findings show that energy and lipid metabolism in CDK12‐deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12‐deficient prostate cancer patients.Key points: CDK12 deficiency promotes castration‐resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12‐deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

Although patients with early localized prostate cancer can survive longer, castration-resistant prostate cancer (CRPC) has gradually emerged with the use of androgen deprivation therapy (ADT). N-Myc and TEM8 play a vital role in the progression of several cancer types. However, the underlying mechanism of how N-Myc and TEM8 promote the progression of prostate cancer remains unclear. In this study, the expression of N-Myc and TEM8 was detected in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissues by immunohistochemistry (IHC). LNCaP cell lines were maintained in RPMI 1640 medium supplemented with 10% charcoal-stripped fetal bovine serum. Subsequently, R language software was used to verify our results. Tubule formation assay of human umbilical vein endothelial cell (HUVEC) was conducted to examine the effect of N-Myc and TEM8 overexpression on angiogenesis in prostate cancer cells. IHC results showed a positive correlation between the expression of N-Myc and TEM8 in prostate cancer tissues. Further analysis showed that N-Myc and TEM8 were associated with clinicopathological features and poor prognosis in prostate cancer patients. Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. Additionally, N-Myc and TEM8 overexpression was associated with therapeutic resistance. We further found that N-Myc promoted angiogenesis and therapeutic resistance in prostate cancer via TEM8. Hence, targeting N-Myc/TEM8 pathway in prostate cancer would be a novel therapeutic strategy to enhance the treatment of prostate cancer patients.

Prostate cancer (PCa) is a prevalent malignancy among men, with a majority of patients presenting with distant metastases at the time of initial diagnosis. These patients are at a heightened risk of developing more aggressive castration‑resistant PCa following androgen deprivation therapy, which poses a greater challenge for treatment. Notably, the inhibition of tumor angiogenesis should not be considered an ineffective treatment strategy. The regulatory role of CDK12 in transcriptional and post‑transcriptional processes is essential for the proper functioning of various cellular processes. In the present study, the expression of CDK12 was first knocked down in cells using CRISPR or siRNA technology. Subsequently, RNA‑seq analysis, co‑immunoprecipitation, western blotting, reverse transcription‑quantitative polymerase chain reaction and the LinkedOmics database were employed to reveal that CDK12 inhibits insulin like growth factor binding protein 3 (IGFBP3). Western blot analysis also demonstrated that CDK12 promoted VEGFA expression by inhibiting IGFBP3, which involves the Akt signaling pathway. Then, CDK12 was found to promote PCa cell proliferation, cell migration and angiogenesis by inhibiting IGFBP3 through cell proliferation assays, cell migration assays and tube formation assays, respectively. Finally, animal experiments were performed for in vivo validation. It was concluded that CDK12 promoted PCa and its angiogenesis by inhibiting IGFBP3.

Prostate cancer (PCa) is an extremely heterogeneous cancer and is highly prevalent in the older male population. Since intra‐tumour heterogeneity (ITH) commonly results in PCa chemotherapy resistance and recurrence, it is critical to explore its effects on tumour behaviour. Prognostic genes related to ITH were identified, and a signature was constructed using Cox regression analyses and multiple machine learning algorithms. Single‐cell RNA sequencing data extracted from PCa and CRPC samples were analysed via sub‐clustering, pseudotime, cell communication and drug sensitivity approaches to elucidate their function. The oncogenic potential of hub genes was confirmed by immunohistochemistry and cell proliferation assays. An 11‐gene signature underlying a prostate cancer meta‐program (PCMP) was generated by selecting an optimal combination of machine learning methods. Survival assays and multivariate Cox regression analyses conducted in multiple cohorts revealed the superior prognostic value of the PCMP signature. Functional enrichment analyses indicated that it dysregulates the cell cycle. Using trajectory and cell–cell communication analyses, we illustrated that PCMP genes exert oncogenic effects by enhancing the proliferation and oxidative phosphorylation of epithelial cells. Intra‐cellular assays also demonstrated that CENPA and CKS1B had promising malignant potential. In summary, our research not only establishes the association between the PCMP signature and reveals its malignant characteristics, but also deepens our understanding of the mechanisms underlying PCa progression and ITH. It holds promise for the development of targeted therapeutic interventions, thereby offering clinical benefits to patients.

This article presents a series of cases involving hepatic lenticular degeneration (Wilson's disease) complicated by renal tumors. It details the clinical manifestations, diagnostic procedures, treatment strategies, pathological features and outcomes of these patients. We found that this type of patient has an early‐onset disease, complex tumor pathological types, and may have a relatively poor prognosis. Through the analysis of these cases, we aim to enhance the understanding of this complex condition and provide valuable references for clinical practice.