androgen receptor
androgen receptor
Overview
The androgen receptor (AR; Wikidata Q416601) is a member of the nuclear receptor superfamily of ligand-activated transcription factors, encoded by the AR gene located on chromosome Xq11–12. Upon binding cognate androgens such as testosterone and its more potent metabolite dihydrotestosterone (DHT), AR undergoes a conformational change, dissociates from cytoplasmic chaperone complexes, and translocates to the nucleus, where it binds androgen response elements (AREs) in target gene promoters and enhancers to drive transcriptional programs governing cell proliferation, survival, and differentiation. AR is an essential mediator of male sexual development and reproductive physiology, but its dysregulated activity has been implicated in a broad spectrum of pathological conditions. Beyond its classical role in the prostate, AR exerts context-dependent effects in other tissues, including hair follicles, the central nervous system, immune cells, and a variety of epithelial cancers.
AR is best recognized as the central oncogenic driver in prostate cancer, where sustained androgen signaling fuels tumor growth even under conditions of systemic androgen deprivation — a state operationally defined as castration-resistant prostate cancer (CRPC). Mechanistically, CRPC exploits diverse resistance mechanisms including AR amplification, gain-of-function mutations, constitutively active splice variants (notably AR-V7), and cistrome reprogramming that rewires AR to activate non-canonical transcriptional networks. These mechanisms have made AR not merely a therapeutic target but a focal point for pharmaceutical innovation, spanning AR antagonists, androgen biosynthesis inhibitors, and, more recently, AR protein degraders. Emerging evidence also implicates AR in tumor immunology, metabolic regulation, and diseases such as androgenetic alopecia (AGA), broadening the therapeutic interest well beyond prostate cancer.
Focus of Latest Publications
Recent studies have continued to position AR as a central node in prostate cancer progression and resistance biology. Several reports focused on castration-resistant disease, emphasizing that CRPC progression relies on AR-driven oncogenic transcription and that advanced tumors often use reprogrammed or noncanonical AR signaling that persists under AR signaling inhibitors (ARSI). One study highlighted MECOM as critical for AR-driven treatment-resistant prostate cancer, linking AR cistrome reprogramming to disease progression. Another study showed that AR-Targeted therapies can sensitize prostate cancer to cuproptosis by transcriptionally activating FDX1, reinforcing the idea that AR blockade may be combined with other lethal stress pathways.
Therapeutic targeting of AR was also explored through multiple drug modalities. Bavdegalutamide (ARV-110) was described as an oral PROTAC androgen receptor degrader in a Phase Ib trial combined with abiraterone for metastatic prostate cancer. Other work examined AR-TAD inhibitors, including efforts to drug the intrinsically disordered transactivation domain of AR, and a cap-binding domain inhibitor strategy that affected AR stability through translational upregulation of the deubiquitinases BAP1 and OTUD3. These studies collectively reflect a shift from conventional receptor antagonism toward degradation, transcriptional interference, and indirect control of AR abundance.
Several publications addressed AR-associated lineage plasticity and neuroendocrine differentiation. In neuroendocrine prostate cancer models, genetic suppression of HOXD11 blocked neuroendocrine differentiation and restored AR signaling, indicating that AR loss or suppression can be intertwined with lineage switching. Another study reported that OGDHL loss altered androgen receptor inhibition-induced plasticity, while a separate analysis of NE prostate cancer used cell line models to examine AR-related differentiation states. These findings underscore the role of AR not only as a growth driver but also as a determinant of tumor lineage identity.
AR was also studied in relation to tumor microenvironment and immune regulation. In male head and neck squamous cell carcinoma, AR signaling was identified as a key regulator of the tumor immune microenvironment by modulating CD8+ T-cell differentiation and function; androgen deprivation therapy reversed this dysfunction. In gastric cancer, multi-omics analysis suggested AR as a potential prognostic factor and immune-related therapeutic target, with interest in its predictive value for immunotherapy response. Related work in prostate cancer also linked AR repression of BCL-2 transcription to therapeutic response, and a phase 3 Alliance A031201 trial context was referenced among studies involving AR pathway inhibition and combination treatment strategies.
Beyond oncology, AR was examined in androgenetic alopecia, where local delivery of AR-targeting siRNA was presented as a promising therapeutic approach. In glioblastoma, enzalutamide was used to enhance honokiol-induced apoptosis in drug-resistant glioblastoma cells, and the role of AR in glioblastoma malignancy was further identified. A separate computational study on lawsone noted no predicted activity on androgen receptors, suggesting minimal hormonal disruption rather than AR engagement. Together, these publications show that AR remains a widely studied target across cancer biology, endocrine pharmacology, and drug safety assessment.