Hai Huang

Resistance to next-generation androgen receptor antagonists represents a major clinical challenge in prostate cancer (PCa), underscoring the need to define its underlying mechanisms. Here, through an integrated analysis of multiple cohorts, we identify PABPC1 as an RNA-binding protein upregulated in therapy-resistant tumors, whose expression correlates with adverse clinicopathological features. Elevated PABPC1 confers enzalutamide (Enz) resistance by suppressing tumor-cell ferroptosis and CD8⁺ T-cell cytotoxicity. Mechanistically, PABPC1 promotes the cytoplasmic colocalization of EIF4A1 with ATF4 mRNA and enhances EIF4A1-associated translation of ATF4 mRNA. Subsequently, ATF4 binds the BCAT1 promoter and transcriptionally upregulates BCAT1, thereby promoting branched-chain amino acid (BCAA) metabolic remodeling and ferroptosis resistance, with leucine emerging as a major functional contributor to both ferroptosis regulation and CD8⁺ T-cell effector responses. In preclinical models, ixazomib restores ferroptotic vulnerability, reinvigorates T-cell activity, and synergizes with Enz, without overt histopathological abnormalities in major organs. These results identify the PABPC1-ATF4-BCAT1 axis as a key regulatory pathway linking RNA regulation with metabolic and immune reprogramming to facilitate treatment resistance in PCa.

Background and Purpose: Lower urinary tract symptoms (LUTS) represent a complex clinical syndrome with significant sexual dimorphism. Traditional “one‐size‐fits‐all” management often overlooks intra‐sex phenotypic heterogeneity. This study utilized unsupervised machine learning to identify sex‐specific digital phenotypes of LUTS within a large‐scale clinical cohort to provide a foundation for precision urological care. Materials and Methods: We analyzed a multicenter database of 1586 treatment‐seeking adults (1098 females, 488 males) across 35 centers. Baseline clinical characteristics and LUTS parameters from standardized voiding diaries and validated scales were collected. K‐means clustering was performed separately by sex to identify phenotypic subtypes, with the optimal number of clusters determined by the Elbow Method and visualized via Principal Component Analysis (PCA). Results: Significant sex‐specific disparities were observed: women reported a higher symptomatic burden across almost all domains but maintained better voiding satisfaction ( p < 0.001), while men exhibited poorer sleep quality ( p < 0.001). Clustering identified a consistent three‐subtype framework for both genders: Subtype 1 (Mild/Compensated): Characterized by the lowest symptom burden and highest tolerance. Subtype 2 (Storage‐Dominant with Sleep Fragmentation): Found in older populations, defined by severe nocturia, reduced bladder capacity, and profound sleep disruption. Subtype 3 (Voiding‐Dominant): Characterized by prominent dysuria and incomplete emptying. Conclusions: This exploratory sex‐stratified clustering study identified symptom‐based phenotypic patterns among treatment‐seeking Chinese adults with LUTS. These findings support the potential value of a subtype‐plus‐sex framework for LUTS assessment, but prospective validation using objective functional measures and treatment outcomes is needed.

Despite the clinical promise of immune checkpoint blockade (ICB), its therapeutic performance in prostate cancer remains suboptimal due to membrane repair‐associated resistance and insufficient immune engagement. Herein, a programmable‐responsive cell‐resident micelle (PBAM) is engineered to integrate BAPTA (a calcium chelator), anti‐PD‐L1 antibody, and prochlorperazine (PCZ)/β‐cyclodextrin inclusion complexes within a pH/granzyme B (GzmB)‐dual‐responsive system, enabling spatiotemporally coordinated multidrug release for integrated anti‐PD‐L1 immunotherapy. PBAM selectively accumulates in tumors and undergoes acid‐triggered PCZ release, suppressing PI3K/Akt signaling and reducing endocytic uptake to maintain tumor cell surface anchoring. Upon ICB‐mediated immune activation, cytotoxic T lymphocytes (CTLs) secrete granzyme and perforin to induce tumor cell apoptosis while triggering GzmB‐responsive micellar degradation for BAPTA release, thereby disrupting Ca ²⁺ ‐dependent membrane repair and sensitizing tumor cells to CTL‐mediated cytotoxicity. This spatiotemporally coordinated cascade reinforces PD‐1/PD‐L1 blockade to overcome immune resistance, thereby restoring antitumor immunity and enhancing memory‐associated T‐cell responses, ultimately constraining tumor progression and recurrence.

Resistance to second‐generation antiandrogens poses a major therapeutic challenge in castration‐resistant prostate cancer (CRPC). While ferroptosis evasion has been implicated in treatment failure, the key molecular determinants driving this evasive process are poorly understood. Using integrated multi‐omics analyses of resistant models and patient specimens, we identify glutathione S‐transferase alpha 4 (GSTA4) as a pivotal ferroptosis suppressor that is associated with adverse clinical outcomes and drives antiandrogen resistance via a dual compartmentalization mechanism. Our data demonstrate that GSTA4 not only detoxifies the lipid peroxidation product 4‐hydroxynonenal in the cytosol but also translocates to the mitochondria under ferroptotic stress. GSTA4 interacts with PGAM5 to prevent the dephosphorylation of Drp1 at Ser637, thereby maintaining mitochondrial fitness and suppressing ferroptosis. This spatially coordinated defense program is crucial for antiandrogen resistance, as GSTA4 knockdown sensitizes tumors to antiandrogen therapy. Virtual screening and surface plasmon resonance assays identify metformin as a candidate GSTA4 inhibitor. Targeting GSTA4 with metformin restores ferroptosis sensitivity and reverses antiandrogen resistance both in vitro and in vivo. Our findings uncover a spatially coordinated anti‐ferroptotic mechanism underlying antiandrogen resistance and highlight targeting GSTA4 as a promising combination strategy for CRPC treatment.

Background: Overactive bladder (OAB) is a prevalent condition that substantially impairs quality of life (QoL); however, the real-world utility of standard behavioral and pharmacological therapies is often limited by poor long-term adherence. Digital interventions have emerged as a promising strategy to provide accessible and personalized support, but their overall efficacy compared with conventional care remains to be systematically established. Objective: This study aimed to evaluate the efficacy of digital interventions compared with conventional care for improving symptoms, QoL, and treatment adherence in patients with OAB. Methods: We conducted a systematic review and meta-analysis using data from PubMed, Embase, the Cochrane Library, and other databases from inception to July 2025. Randomized controlled trials (RCTs) assessing technology-based digital interventions for adult patients with OAB were included. The primary outcomes were objective symptom improvement (measured by bladder diaries) and subjective symptom scores, while secondary outcomes included QoL and attrition rates. Data were pooled using a random-effects model, and subgroup analyses were performed according to the delivery and supervision category (automated or app-based therapeutic content, telemedicine-supported care management, or digitally supervised behavioral or rehabilitation support) and intervention duration. Results: Seven RCTs involving 544 participants were included. Digital interventions were associated with a significant improvement in overall objective symptom indicators compared with conventional care (mean difference [MD] −1.72, 95% CI −2.61 to −0.83; P<.001), specifically reducing 24-hour urinary frequency (MD −2.55, 95% CI −4.22 to −0.89; P=.003) and urge incontinence episodes (MD −2.07, 95% CI −2.72 to −1.42; P<.001). The pooled analysis of subjective symptom scores did not reach statistical significance (standardized MD [SMD] −1.07, 95% CI −2.18 to 0.05; P=.06). Exploratory subgroup analysis suggested that digitally supervised behavioral or rehabilitation support had the largest point estimate (SMD −2.51, 95% CI −5.03 to 0.01), although the CI crossed the line of no effect, and the finding was based on 2 heterogeneous studies. The prespecified subgroup analysis by intervention duration showed that interventions lasting 6 to 13 weeks were associated with symptom reduction (SMD −1.41, 95% CI −2.70 to −0.11; P=.03), suggesting a potentially favorable duration range. Furthermore, digital interventions significantly improved QoL (SMD 1.47, 95% CI 0.11-2.84; P=.03). No significant difference was observed in dropout rates between digital and conventional care groups (risk ratio 0.92, 95% CI 0.59 to 1.45; P=.72). Conclusions: Digital interventions may improve objective symptoms and QoL in patients with OAB, with comparable short-term attrition to conventional care. Interventions with higher-intensity digital supervision may have potential for symptom reduction, but this finding remains uncertain because of the small number of heterogeneous studies. These findings may inform future stepped care models, but further well-designed, longer-term RCTs are needed to confirm optimal implementation strategies. Trial Registration: PROSPERO CRD420251164488; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251164488

Prostate cancer (PCa) is characterized by significant metabolic heterogeneity, particularly in glutathione (GSH) metabolism. Elevated GSH metabolism is closely linked to PCa progression, therapeutic resistance, and poor clinical outcomes. Recent studies have highlighted the impact of protein butyrylation on cancer biology, although related therapeutic strategies remain limited. Herein, we utilized a cysteine‐based, GSH‐responsive polymer (Cys8E) to deliver a broad‐spectrum antitumor agent CBL0137. Exploiting high GSH levels in PCa cells, the resulting CBL0137‐loaded nanoparticles (Cys8E@CBL NPs) achieved targeted and efficient intracellular delivery and enhanced tumor‐killing efficacy. Mechanistic investigations revealed that upon internalization by tumor cells, Cys8E NPs perturbed butyrate‐associated metabolic homeostasis, as reflected by altered abundance of related metabolic enzymes and increased intracellular protein butyrylation levels. This metabolic remodeling was accompanied by enhanced lysine‐95 butyrylation of PGAM5, which promoted necroptosis. Collectively, these findings define Cys8E@CBL NPs as a redox‐responsive formulation in which the carrier contributes to therapy not only by improving CBL0137 delivery but also by reshaping butyrate‐associated metabolism. This process promotes PGAM5 K95 butyrylation and strengthens necroptotic tumor cell killing. These results extend the design rationale of nanomedicine from passive payload transport toward active regulation of metabolism‐dependent post‐translational signaling in prostate cancer.

Prostate cancer (PCa) is frequently accompanied by benign prostatic hyperplasia (BPH), highlighting the need to reassess their correlation in tumor risk, malignant progression, and immune status to improve the early diagnosis and treatment of PCa. In this study, single‐cell RNA sequencing and spatial transcriptomics were used to analyze the potential association between normal, BPH, and PCa tissues. Our study revealed a continuous transformation map of luminal epithelial cells from hyperplasia to malignancy in BPH and PCa, accompanied by a persistently suppressive immune microenvironment. In the lesion nodules, T cells showed a high degree of infiltration yet showed activation retardation and functional exhaustion. Macrophages were also significantly infiltrated, exhibiting significant M2 polarization characteristics, and inflammatory signaling pathways related to immune escape were activated. Natural killer (NK) cells and B cells were partially activated, yet the low abundance of NK cells and B cells resulted in functional limitations. Our results revealed the dynamic changes of the immune landscape during the occurrence and progression of PCa. Our classification and prognostic models provide a theoretical basis for immunomodulatory and personalized therapies and provide new tools for the early diagnosis and intervention of PCa.

Microbial contributions to prostate health and disease extend beyond the mere detection of organisms in urine or tissue. Rather than acting as stable colonisers, microbial influences on the prostate are better conceptualised as converging fluxes: systemically circulating gut-derived metabolites, immune education occurring in distal lymphoid compartments, and intermittent exposure to microbial products from the lower urinary tract. These inputs converge on a limited set of conserved mediator–receptor axes—including short-chain fatty acids, bile acids and indole derivatives—that calibrate epithelial barrier integrity, inflammatory thresholds, antigen-presentation capacity and myeloid cell fate. Crucially, the biological relevance of these axes is stage-dependent. In benign prostatic hyperplasia and chronic prostatitis/chronic pelvic pain syndrome, metabolite tone shapes inflammatory activation thresholds and barrier resilience. In localized prostate cancer, these same pathways intersect with antigen-processing machinery and immune exclusion. In castration-resistant disease, tumour-intrinsic metabolic plasticity and redox balance predominate, with microbial and host-derived metabolites assuming relevance when they modulate lipid remodelling and ferroptotic vulnerability. Interpretation is constrained by the intrinsically low biomass of urine and prostate tissue. Robust inference therefore requires quantitative anchoring, orthogonal validation and explicit separation of association from causality. Translational progress is most likely to emerge from calibrated measurement and stage-aware modulation rather than indiscriminate ecological manipulation. By integrating mechanistic, spatial and clinical evidence, this Review proposes a stage-aware framework for the gut–urinary–prostatic axis and delineates when microbial and metabolite signalling meaningfully conditions prostate disease biology—and when it does not.

Pharmacological innovation for benign prostatic hyperplasia (BPH) has stagnated. As disease burden rises, whether trial activity is addressing disease-modifying therapy remains unclear, while the published literature captures only reported successes. We reviewed BPH drug trial registrations in ClinicalTrials.gov and ChiCTR (2000–2025), standardized design, phase, status, mechanism, and result-reporting variables, and analyzed 224 eligible trials. Of these, 211 were non-ongoing, but only 55.0% had publicly available results. Among 43 studies targeting prostate volume reduction, 25 (58.1%) reported results and 12 (48.0%) showed efficacy; among 137 targeting volume-independent symptom improvement, 82 (59.9%) reported results and 63 (76.8%) showed efficacy. Classical mechanisms, including α1-adrenergic antagonists (24.6%) and 5α-reductase inhibitors (8.5%), dominated Phase III/IV trials (51.9% and 61.1%), whereas emerging mechanisms were concentrated in Phase I/II trials, accounting for 20.0–50.0% of early-phase research. Most trials evaluated single agents (78.6%), while combination and head-to-head studies were uncommon. Industry sponsorship predicted result disclosure (OR 6.67; P < 0.001); mechanism was associated with reporting overall (P = 0.02) and borderline in Phase III (P = 0.05); enrollment ratio was associated in Phase II (OR 13.97; P = 0.04). BPH drug development remains trapped in symptomatic relief, with limited disease modification and substantial hidden failure, requiring greater priority for disease-modifying mechanisms, transparency, and societal and industry investment.