Androgen receptor (AR) is a therapeutic target for prostate cancer. Despite effectively targeting its folded ligand-binding domain (LBD), resistance ultimately develops by mechanisms involving reactivation of AR signaling. These mechanisms include expression of constitutively active AR that lacks LBD and fueled the discovery of inhibitors that bind to AR’s N-terminal intrinsically disordered transactivation domain (TAD). AR-TAD inhibitors (ARTADIs) are unique due to the paucity of small molecule inhibitors that bind directly to intrinsically disordered TADs, which have historically been considered undruggable. Leveraging our library of ARTADIs using cultured prostate cancer cells and multiple xenograft models, we reveal that small alterations in the chemical scaffold impact selectivity and potency within the AR-transcriptome; impacting signal transduction pathways involved in protumorigenic mechanisms. Mechanistically, these compounds differentially disrupt interactions between full-length AR or splice-variant AR-V7, and co-regulators, as revealed by rapid immunoprecipitation mass spectrometry of endogenous protein and the proximity ligation assay. Biophysically, several ARTADIs displayed exceptionally strong binding affinities that were better than, or were comparable to the LBD-inhibitor enzalutamide, with dissociation constants in the picomolar to low-nanomolar range as determined by surface plasmon resonance and microscale thermophoresis. MS/MS analysis revealed covalent binding to cysteine 129. In vivo, ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. These findings support the feasibility - but also highlight the complexity - of developing drugs against an intrinsically disordered TAD impacted by multivalent binding interactions that may not occur in a stepwise fashion.

Abstract Molecular glue degraders (MGDs) offer a sophisticated, proximity-based approach to protein modulation. In this study, we introduce LJY-3-60, a novel proximity-inducing agent that unexpectedly triggers the potent and selective autodegradation of CRBN. Evidence from CRISPR-Cas9 screening and IP-MS reveals that this degradation process is strictly governed by the intrinsic CRL4 CRBN machinery, independent of any extrinsic E3 recruitment. Through a combination of cellular and biophysical characterizations, we demonstrate that LJY-3-60 acts as a molecular bridge to template CRBN homodimerization. This mechanism is unequivocally elucidated by the atomic-resolution co-crystal structure of the CRBN Midi -LJY-3-60 complex. The structure explicitly delineates the homodimerization interface, revealing how the ligand reorganizes the protein surface to stabilize a non-canonical architecture that drives trans-autoubiquitination and subsequent proteasomal degradation. Furthermore, LJY-3-60 serves as a highly effective, controllable off-switch to mitigate PROTAC-induced toxicity. Ultimately, this work delivers a robust chemical tool for modulating CRBN stability. By demonstrating how a small molecule can functionally mimic an endogenous E3 substrate’s degron to catalyse targeted autodegradation, this study establishes a rational structural framework for designing the next generation of self-destructive modulators in targeted protein degradation (TPD) therapeutics.

Abstract Solid tumors remain refractory to conventional treatments, yet cell surface proteins, by virtue of their extracellular accessibility and critical roles in tumor signaling, represent an attractive class of targets for precision-targeted therapy. Here, we report that transmembrane protein 132A (TMEM132A) is an essential and previously unrecognized pan-cancer target. TMEM132A interacts directly with EGFR and stabilizes its expression, thereby tethering EGFR at the plasma membrane and sustaining constitutive activation of lipid synthesis. Mechanistically, the TMEM132A-EGFR axis promotes lipogenesis by facilitating SREBP nuclear translocation, which in turn upregulates ACLY and ACSS2 expression to drive acetyl-CoA production and downstream lipid biosynthesis, ultimately disrupting lipid droplet homeostasis. To therapeutically target this axis, we developed a nanobody, LFNanoT132A#3, which effectively blocks the TMEM132A-EGFR interaction, abrogates downstream signaling activation, and potently inhibits proliferation across multiple solid tumor types. Our findings establish TMEM132A#3 as a critical node in membrane-tethered oncogenic signaling and metabolic rewiring, and position LFNanoT132A#3 as a promising therapeutic candidate for precision cancer therapy.

Aging is a systemic biological process that spans multiple levels, including molecules, cells, tissues, and organs. Cellular senescence is regarded as one of the key mechanisms driving functional decline, chronic inflammation, and the onset and progression of ageu2010related diseases. Among the numerous biomarkers of senescence, senescenceu2010associated u03B2u2010galactosidase (SAu2010u03B2u2010gal) has become one of the most widely used classical indicators in cellular senescence research. However, conventional Xu2010gal staining and lysateu2010based assays largely rely on endpoint, ex vivo, or semiu2010quantitative readouts, making it difficult to meet the growing demand for realu2010time, in situ, dynamic, and highly sensitive visualization of senescent states in live cells, tissue sections, and living organisms. The development of fluorescence imaging technologies, particularly nearu2010infrared fluorescence imaging, has provided a new toolkit for detecting SAu2010u03B2u2010gal activity. Fluorescent probes containing a u03B2u2010Du2010galactose unit can be activated by u03B2u2010galactosidase, resulting in the recovery or change of fluorescence signals. This review systematically summarizes recent advances in senescence imaging targeting SAu2010u03B2u2010gal, including turnu2010on probes, ratiometric probes, AIEu2010based probes, and nanoprobes. In particular, we highlight strategies to improve the specificity of SAu2010u03B2u2010gal imaging, enhance the ability to distinguish SAu2010u03B2u2010gal activity in senescent cells from that in nonu2010senescent tumor cells, and further discuss the challenges and opportunities in this field.

BACKGROUND:Radiographic progression-free survival (rPFS) in prostate cancer (PC) may not always accurately reflect tumor progression. However, the prognostic significance of osteosclerotic changes (OCs) in PC remains unclear. METHODS:A training cohort of 152 PC patients with osteoblastic metastases was recruited from the Sun Yat-sen University Cancer Center, while a validation cohort of 41 patients was obtained from two additional hospitals. Patients were stratified into two groups based on computed tomography findings: those with OCs and those without OCs (no osteosclerotic change [NOC]). Clinical outcomes were subsequently analyzed. RESULTS:In the training cohort, 103 and 49 patients were classified into the OC and NOC groups, respectively. A significantly higher proportion of radiographic progression was observed in the OC group than in the NOC group (72.8% vs. 51.0%, P  = 0.0105). The OC group demonstrated significantly worse rPFS and overall survival (OS) than the NOC group (median rPFS: 11.6 months vs. 52.9 months, P < 0.0001, median OS: 30.7 months vs. 67.1 months, P < 0.0001). Multivariate analysis identified OC as an independent prognostic factor for poor rPFS and OS. The results were validated in an external cohort. CONCLUSION:OCs are associated with adverse survival outcomes and may serve as potential biomarkers for disease progression and reduced survival in PC patients with osteoblastic metastases.

BACKGROUND:Lymphoma poses a significant public health challenge with complex subtypes. While obesity and adipokines have been linked to lymphoma, causal relationships remain unclear. This study uses Mendelian randomization (MR) to systematically assess these associations. RESEARCH DESIGN AND METHODS:Two-sample MR analyzed genetic data from genome-wide association studies to evaluate causal links between obesity, adipokines (adiponectin, leptin, and resistin), and lymphoma subtypes (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin lymphoma, and other unspecified types of non-Hodgkin lymphoma). Primary analysis used inverse variance weighted (IVW), supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses (MR-Egger regression, Cochran's Q test, MR-PRESSO, leave-one-out) and linkage disequilibrium score regression (LDSC) ensured robustness. RESULTS:IVW revealed obesity positively associated with follicular lymphoma (OR = 1.352, 95% CI: 1.095-1.670, p = 0.005) and other unspecified types of non-Hodgkin lymphoma (OR = 1.297, 95% CI: 1.050-1.603, p = 0.016). No significant links were found between adipokines and lymphoma. Sensitivity analyses confirmed no heterogeneity or pleiotropy. CONCLUSIONS:Obesity may independently increase lymphoma risk, unrelated to adipokines. These findings highlight new risk factors, urging further research into pathological mechanisms and biomarkers.

BACKGROUND:Ranolazine is a highly effective inhibitor of the late sodium current and has been received approval from the FDA in 2006 for the treatment of chronic angina. To date, nearly 2000 papers have been published on it. It has demonstrated therapeutic potential in various fields, but uncertainties regarding its efficacy, safety risks, and limitations in expanding indications have hindered its clinical application. Therefore, we believe that the current period is the best time to conduct bibliometric analysis to overcome existing challenges and optimize interdisciplinary strategies. METHODS:We searched and downloaded the papers in the Science Citation Index Expanded database of the Web of Science Core Collection on September 1, 2025. Microsoft Excel was applied to organize the data, WeiShengXin, CiteSpace and VOS viewer were used for data analysis and visualization. RESULTS:A total of 1121 papers were included for follow-up research. The USA is the most productive country in this field and serves as a central hub for global cooperation and exchange. Gilead Sciences is the institution with the highest output in this field. Professor Belardinelli, L and Professor Chaitman, BR are the most influential authors in this field. The keywords "efficacy," "ventricular arrhythmias," "impact" and "channels" still have a strong influence at present. CONCLUSIONS:Currently, the research focus in this field primarily centers on 3 key aspects: the anti-angina effect, the electrophysiological characteristics and anti-arrhythmic effect and other effects of ranolazine. The future research direction in this field is likely to focus on the neuroprotective effect of ranolazine, its antitumor metastasis effect and its effect on atrial fibrillation and diabetes patients on the basis of maintaining the current research focus.

Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses. Through comparison between sensitive and insensitive cell lines, we revealed that STAT1 can be regarded as a biomarker for STAT3 PROTAC degrader, which was validated in cells, patient-derived organoids, and mouse models. These results set an example for a comprehensive description of the multidimensional PROTAC pharmacodynamic response and PROTAC drug sensitivity biomarker exploration.

This supplementary table lists the differentially methylated CpG probes (DMPs) induced by DNMT3A_R882H in TF-1 cells.

Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation-related markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and simultaneous suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2's both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.

This Supplementary Figure S5 shows that DNMT3A hotspot mutation is associated to CpG hypomethylation of LMO2.

<p>This file contains Supplementary Figure S6, demonstrating that bromodomain inhibition suppressed AML related to DNMT3A hotspot mutation in murine models.</p>

<p>This contains Supplementary Figure S1, which shows transformation of TF1 cells by R882-mutated DNMT3A.</p>

<p>This document includes sections of Supplementary Methods and Material, Supplementary Figures Legends and related references</p>

Evaluating the protection effectiveness of natural protected areas is an important step in successful management. Adopting 330 natural protected areas on the Qinghai–Tibet Plateau as research subjects, the regional dominant ecosystem service function was selected, and various temporal and spatial analysis methods were employed to analyze the evolution characteristics and influencing factors of ecosystem service patterns from 2000 to 2020. Our results indicated that (1) the water conservation function stabilized after fluctuation and decline, the soil conservation function fluctuated upward, and the windbreak and sand fixation function exhibited an increase after a decreasing fluctuation. (2) The protection effectiveness of25 protected areas significantly improved, that of 151 protected areas improved, that of 84 protected areas stabilized, that of 56 protected areas worsened, and that of 14 protected areas significantly worsened. (3) The top three influencing factors in descending order were precipitation change > altitude > mining area density. (4) Remarkable protection results were achieved in national protected areas, established management institutions, earlier established areas (before 2000), and areas exhibiting alow built-up area density (<0.75%) and low mining density (<1%). Our study provides technical support for the construction and management of protected areas and improvement in ecosystem service functions on the Qinghai–Tibet Plateau.

Transcription factors are among the most attractive therapeutic targets but are considered largely ‘undruggable’ in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

<p>This contains Supplementary Figure S2, which reveals CpG hypomethylation included by DNMT3A hotspot mutations.</p>

Primer Sequence for Real-time PCR from Crosstalk between the Androgen Receptor and β-Catenin in Castrate-Resistant Prostate Cancer

This contains Supplementary Figure S3, which shows dose-dependent effect by DNMT3A hotspot mutation on transformation and CpG hypomethylation.