Hepatic ischemia–reperfusion (IR) injury is a major complication of liver transplantation, often leading to graft dysfunction and poor outcomes. Sterile inflammation involving diverse immune cells is a hallmark of hepatic IR injury, but the molecular mechanisms of their functions remain incompletely understood. Our single-cell RNA sequencing (scRNA-seq) analyses revealed an upregulation of Ptgs2 (the gene encoding cyclooxygenase-2, COX-2), which was predominantly expressed by neutrophils among hepatic immune cells after IR injury. Notably, neutrophil-specific deletion of Ptgs2 exacerbated hepatic IR injury. Interestingly, this effect was observed only in female mice, but not males. Ovariectomy and estrogen supplementation experiments further confirmed an estrogen-dependent protective function of neutrophil-derived COX-2. Mechanistically, we found that neutrophils from female mice exhibited higher COX-2 expression and greater prostacyclin (PGI2) production than those from male mice. Pharmacological administration of a PGI2 analog or blockade of the PGI2 receptor demonstrated that the protective effect of PGI2 was mediated through the induction of heme oxygenase-1 (HO-1) during liver IR injury. In conclusion, our findings reveal a previously unrecognized neutrophil-specific and female-restricted protective function of COX-2 signaling, dependent on estrogen and associated with activation of the COX-2/PGI2/HO-1 pathway, in hepatic IR injury. These findings provide new mechanistic insights into the pathophysiology of IR injury and highlight potential therapeutic strategies for improving outcomes in liver transplantation.

BACKGROUND:Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality during viral pneumonia, including SARS-CoV-2 infections. Nevertheless, most patients with SARS-CoV-2 infections recover seamlessly without developing ARDS, suggesting the existence of endogenous pathways to protect the lungs. Since microRNAs (miRNAs) can regulate endogenous molecular pathways involved in lung protection, the authors hypothesized that alveolar miRNAs could function to dampen SARS-CoV-2-associated lung injury. METHODS:Screening studies in human alveolar epithelial cells and SARS-CoV-2-infected mice were performed to identify miRNAs induced during infection. Candidate miRNAs were confirmed via reverse-transcription quantitative polymerase chain reaction. The role of hypoxia-inducible factor 1α in regulating miRNA expression was examined in molecular studies. Loss- and gain-of-function approaches in a murine SARS-CoV-2-associated ARDS model were used to assess the physiologic relevance of miRNA. Viral sequence analyses and site-directed mutagenesis were used to determine direct miRNA-viral RNA interactions. RESULTS:Screening studies identified miR-147b (hsa-miR-147b-3p or mmu-miR-147-3p) as the leading candidate during infection of human alveolar epithelia or mice with SARS-CoV-2. Functional and molecular studies implicate hypoxia-inducible factor 1α in miR-147b induction during alveolar injury or SARS-CoV-2 infection. Studies in mice with induced deletion of miR-147b in alveolar epithelia ( miR147 fl/fl Sftpc-CreER T2 (SPC-CreER) mice) or nanoparticle-mediated miR-147b overexpression revealed a protective role of alveolar-expressed miR-147b during murine SARS-CoV-2-associated ARDS. Moreover, the authors identified the Open Reading Frame 8 ( ORF8 ) region within the SARS-CoV-2 template strand as a direct target of miR-147b, with an ORF8 silent mutation of the SARS-CoV-2 miR-147b-binding site abolishing the observed protection in vitro and in vivo . CONCLUSIONS:Alveolar epithelial cell-derived miR-147b serves as an endogenous lung protective miRNA against SARS-CoV-2-associated ARDS by directly targeting virus-encoded RNA, revealing a previously unrecognized antiviral and lung-protective mechanism.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition driven by uncontrolled inflammation and immune dysregulation. The post-transcriptional mechanisms that fine-tune macrophage activation in ARDS remain poorly understood. Here, we identify Nudix hydrolase 21 (NUDT21) as a critical regulator of macrophage-mediated inflammation through alternative polyadenylation (APA). NUDT21 was downregulated in macrophages from human and mouse ARDS lungs. Functional studies using macrophage-specific Nudt21 knockout mice (Nudt21f/fLysmCre, Nudt21f/fCxcr1Cre, or mice with bone marrow transplantation) revealed that Nudt21 loss amplifies cytokine production, neutrophil infiltration, and lung injury in lipopolysaccharide or bleomycin-induced lung injury models. Notably, neutrophil depletion did not alleviate the exaggerated inflammation in Nudt21f/fLysmCre mice, confirming a macrophage-specific mechanism. In contrast, Nudt21f/fCD68 rtTA/tetOCre mice did not exhibit increased injury, likely because alveolar macrophages-but not recruited macrophages-play a major role in the LPS model. Transcriptome profiling revealed widespread 3'UTR shortening of inflammatory genes and elevated protein expression in NUDT21-deficient macrophages, indicating APA-mediated translational activation. Furthermore, we identified hypoxia-induced microRNA-181a as an upstream repressor of NUDT21, linking oxygen stress to APA remodeling. Collectively, these findings uncover a previously unrecognized hypoxia-miR-181a-NUDT21-APA axis that amplifies macrophage inflammation and lung injury.

OBJECTIVE:Overactive bladder, a storage syndrome characterized by urinary urgency, frequency, and nocturia with or without urgency urinary incontinence, severely affects the quality of life of patients. The aim of this study was to investigate the role and mechanism of the C/EBP homologous protein in the overactive bladder. METHODS:An overactive bladder mouse model was established via the intraperitoneal injection of cyclophosphamide in wild-type and Chop-deficient mice. An in vitro model was established using interleukin (IL)-6-induced mouse bladder epithelial cells. Hematoxylin-eosin (HE) staining was used to assess bladder tissue damage, and ELISA was used to measure inflammatory cytokine levels. Western blot analysis was used to examine p-PERK, ATF-6, p-eIF2α, BiP, ATF-4, Bax, Bcl-2, and cleaved caspase-3 protein expression levels. TUNEL staining and flow cytometry were conducted to measure the degree of apoptosis in bladder epithelial cells and macrophages. RESULTS:C/EBP homologous protein levels were decreased in overactive bladder tissues; nevertheless, macrophage infiltration was found to be increased. Knockout of Chop exacerbated bladder dysfunction, tissue injury, macrophage infiltration, and bladder epithelial apoptosis and alleviated endoplasmic reticulum stress. CONCLUSIONS:Chop deficiency exacerbates inflammation, injury, and bladder epithelial apoptosis in overactive bladder model mice by inhibiting endoplasmic reticulum stress.

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher (n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We therefore tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF-stabilizer vadadustat. Subsequent studies in genetic models implicated alveolar-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase 2 trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n=448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the two groups. Vadadustat treatment induced surrogate HIF-target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline FiO2 ≥ 80% (n=106), the estimated probability of the primary outcome was 12.1% (vadadustat) vs. 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.

Acute respiratory distress syndrome (ARDS) causes morbidity and mortality during SARS-CoV-2 infections. Nevertheless, most patients with SARS-CoV-2 infection recover seamlessly without developing ARDS. Here, we hypothesized a functional role of microRNAs (miRNAs) in endogenous lung protection during SARS-CoV-2-associated ARDS. Screening studies identified miR-147b (hsa-miR-147b-3p or mmu-miR-147-3p) as the lead candidate during murine and human SARS-CoV-2 infections. Functional molecular studies implicate hypoxia-inducible factor 1A (HIF1A) in miR-147b induction. Subsequent loss-and-gain-of-function studies revealed a protective role of alveolar-expressed miR-147b during murine SARS-CoV-2-associated ARDS. Proof-of-principle studies in patients also implicate this pathway during SARS-CoV-2 infection. Finally, we identified SARS-CoV-2 ORF8 as a direct miR-147b target, and silent mutation of the viral miR-147b-binding site within ORF-8 abolished the observed protection. Together, our findings identify a previously unrecognized role of miR-147b in attenuating SARS-CoV-2-associated lung disease by targeting the viral genome. R01HL154720, R01DK122796, R01HL133900, R01HL155950, R01HL169519, T32GM135118; Department of Defense Grant W81XWH2110032; Parker B. Francis Fellowship; American Lung Association Catalyst Award CA-622265. Viral Immunology (VIR)

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% ( n = 393,157), and 4.4% of cases ( n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated with the lowest mortality (10.8%). This was followed by acute myocardial infarction (incidence 0.6%, mortality 15.6%), stroke (incidence 0.6%, mortality 13.1%), pulmonary embolism (incidence 0.3%, mortality 20.0%), liver injury (incidence 0.1%, mortality 68.7%), and acute respiratory distress syndrome (incidence 0.1%, mortality 44.7%). These findings help prioritize interventions for preventing or treating individual types of perioperative organ injury.

We aimed to explore novel pathogenesis in young children with allergic rhinitis (AR), and thus finding novel nasal spray reagents for them, especially under 4 yr old. In this study, nontargeted metabolomics analyses were used to explore the differential metabolites in nasal lavage fluid (NALF) of children with AR. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to assess cell proliferation and apoptosis in human nasal mucosal epithelial cells (HNEpCs). HNEpCs were cocultured with CD4+ T cells, and flow cytometry was used to detect Th17/regulatory T (Treg) cells. RNA sequencing was used to assess the key pathways in xanthine-treated Jurkat T cells. Finally, both the in vitro and in vivo experiments were used to assess the effect of 1, 3-dipropyl-8 cyclopentylxanthine (DPCPX, Adora1 inhibitor) on activating transcription factor 4 (ATF4) expression and Th17/Treg cells. Xanthine and uric acid levels were increased in the NALF of children with AR. Xanthine dehydrogenase (XDH), purine nucleoside phosphatase (PNP), xanthine/hypoxanthine, and uric acid levels were elevated in Derp1-treated HNEpCs, and si-XDH reversed the reduced cell viability and increased cell apoptosis in Derp1-treated HNEpCs. Both xanthine and Derp1-treated HNEpCs increased the Th17/Treg ratio. The endoplasmic reticulum stress (ERS) pathway was affected in xanthine-treated Jurkat T cells, and ATF4 was markedly reduced in xanthine-treated Jurkat T cells. Xanthine exhibited no effect on Adora1 expression, whereas DPCPX elevated ATF4 expression and reduced the Th17/Treg ratio in xanthine-treated Jurkat T cells. The in vitro experiments revealed that DPCPX reduced inflammatory infiltration, Th17/Treg ratio, interleukin (IL)-17, tumor necrosis factor (TNF)-α, and IL-6 in AR mice. These results demonstrated that xanthine inhibited ATF4 expression via Adora1 to elevate the Th17/Treg ratio in the nasal cavity, thus participating in AR progression. These findings may provide novel therapeutic interventions for young children with AR.NEW & NOTEWORTHY Current nasal spray hormones exhibited some adverse reactions for young children with allergic rhinitis (AR), and there were no suitable nasal spray hormones for children with AR under 4 yr old. This study emphasized the important role of purine metabolism in the nasal cavity in children with AR and provided novel therapeutic interventions for children with AR.

This study evaluated the efficacy and safety of a non-ablative vaginal Er: YAG laser device in treating stress urinary incontinence (SUI). We conducted a prospective, multicenter, randomized, sham-controlled clinical trial in which women with SUI received either active treatment with Er: YAG laser therapy or sham control with a non-therapeutic handpiece. Patients underwent three treatments spaced one month apart. The primary endpoint measure was the treatment success rate at three months post-treatment. A total of 126 participants with SUI were recruited, with 84 in the active arm and 42 in the sham arm. One participant in the sham arm was excluded due to not using research instruments. The treatment success rate at three months post-treatment was 36.59% in the sham arm and 71.43% in the active arm, with an absolute difference of 34.84% (95% CI: 17.2-52.5%). Incontinence quality of life questionnaire (I-QOL) score and incontinence questionnaire short form (ICIQ-SF) score demonstrated significant improvement in the both arms with no substantial difference between the groups. Non-ablative vaginal ErYAG laser therapy demonstrated a significant improvement in objectively measured SUI symptoms compared to sham treatment. The non-ablative Er: YAG laser therapy seems to be a promising non-surgical treatment option for SUI patients. The limitations of this study are the short follow-up and limited sample size, so additional studies with longer follow-up and larger number of patients are needed to further elucidate the role of this therapy for SUI.

Hepatic ischemia–reperfusion injury (H-IRI) is a critical complication in liver surgery and liver transplantation, contributing to graft dysfunction and poor clinical outcomes. When hepatocyte protective mechanisms are insufficient to counteract energy depletion and oxidative stress during ischemia, cell death occurs. Tissue damage during H-IRI leads to the release of damage-associated molecular patterns (DAMPs), which recruit and activate immune cells such as neutrophils and monocytes, orchestrating the initiation, progression, and eventual resolution of sterile inflammation. Extended criteria donor (ECD) livers, particularly steatotic ones, are more vulnerable to H-IRI, leading to poorer outcomes and limiting expansion of the donor pool. However, the mechanisms underlying this increased vulnerability are not yet fully understood. Emerging therapeutic strategies, including machine perfusion technologies, ischemic preconditioning, pharmacological interventions, and others, offer promise for mitigating H-IRI by either attenuating early injury triggers, enhancing intrinsic survival pathways, or restraining excessive inflammatory responses. Despite considerable progress in understanding H-IRI, further research is needed to identify additional therapeutic targets, particularly in the context of ECD livers, to develop effective, targeted interventions that can improve clinical outcomes.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and reduced type I interferon responses and revealed Ndufa4 as a likely miR147 target. Ndufa4, a mitochondrial protein regulating energy metabolism and inflammation, was elevated at the crypt base, inversely correlating with miR147. Mice lacking the miR147 binding site in Ndufa4's 3 '-UTR phenocopied miR147-deficient mice during colitis. Spatial and single-cell transcriptomic analyses in murine and human colons showed mutually exclusive miR147 and Ndufa4 expression, consistent with a regulatory relationship in epithelial differentiation and metabolism. These findings underscore miR147's role in intestinal homeostasis and mucosal healing, suggesting it as a therapeutic target for inflammatory bowel disease.

CD8+ T cells play a pivotal role in antiviral and antitumor immunity, yet under chronic antigen stimulation, they progressively enter a functionally impaired “exhausted” state, characterized by loss of effector functions, sustained high expression of inhibitory receptors, and a distinct transcriptional and epigenetic landscape. Recent studies have highlighted that epigenetic regulation is central to the initiation and maintenance of CD8+ T cell exhaustion. Exhausted T cells exhibit chromatin landscapes markedly different from those of effector and memory T cells, displaying an “epigenetic locking” that renders their phenotype largely irreversible. Emerging evidence highlights the central role of epigenetic and transcriptional regulation in driving and maintaining CD8+ T cell exhaustion. DNA methylation and histone modifications establish stable repressive chromatin landscapes that suppress effector gene programs. Non-coding RNAs, including microRNAs and long non-coding RNAs, fine-tune exhaustion-associated pathways post-transcriptionally, while RNA epigenetic modifications, such as m6A methylation, regulate transcript stability and translation in exhausted T cells. Transcription factors orchestrate these epigenetic and post-transcriptional networks, reinforcing exhaustion-specific gene expression profiles. Together, these interconnected mechanisms not only define the exhausted phenotype but also contribute to tumor immune evasion and therapeutic resistance. Understanding these processes provides a framework for novel strategies aimed at reversing CD8+ T cell exhaustion and improving the efficacy of cancer immunotherapy. Collectively, elucidating the epigenetic mechanisms underlying CD8+ T cell exhaustion not only deepens our understanding of its molecular basis but also provides new avenues for precision immunotherapy and individualized interventions.

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia.

The human respiratory and circulatory systems collaborate intricately to ensure oxygen delivery to all cells, which is vital for ATP production and maintaining physiological functions and structures. During limited oxygen availability, hypoxia-inducible factors (HIFs) are stabilized and play a fundamental role in maintaining cellular processes for hypoxia adaptation. First discovered during investigations of erythropoietin production regulation, HIFs influence physiological and pathological processes, including development, inflammation, wound healing, and cancer. HIFs promote extracellular adenosine signaling by enhancing adenosine generation and receptor signaling, representing an endogenous feedback mechanism that curbs excessive inflammation, supports injury resolution, and enhances hypoxia tolerance. This is especially important for conditions that involve tissue hypoxia, such as acute respiratory distress syndrome (ARDS), which globally poses significant health challenges without specific treatment options. Consequently, pharmacological strategies to amplify HIF-mediated adenosine production and receptor signaling are of great importance.

Abstract Background The efficacy of surgical treatment for benign prostatic hyperplasia (BPH) patients with detrusor underactivity (DU) remains controversial. Methods To summarize relevant evidence, three databases (PubMed, Embase, and Web of Science) were searched from database inception to May 1, 2023. Transurethral surgical treatment modalities include transurethral prostatectomy (TURP), photoselective vaporization of the prostate (PVP), and transurethral incision of the prostate (TUIP). The efficacy of the transurethral surgical treatment was assessed according to maximal flow rate on uroflowmetry (Qmax), International Prostate Symptom Score (IPSS), postvoid residual (PVR), quality of life (QoL), voided volume, bladder contractility index (BCI) and maximal detrusor pressure at maximal flow rate (PdetQmax). Pooled mean differences (MDs) were used as summary statistics for comparison. The quality of enrolled studies was evaluated by using the Newcastle–Ottawa Scale. Sensitivity analysis and funnel plots were applied to assess possible biases. Results In this study, 10 studies with a total of 1142 patients enrolled. In BPH patients with DU, within half a year, significant improvements in Qmax (pooled MD, 4.79; 95% CI, 2.43–7.16; P < 0.05), IPSS(pooled MD, − 14.29; 95%CI, − 16.67–11.90; P < 0.05), QoL (pooled MD, − 1.57; 95% CI, − 2.37–0.78; P < 0.05), voided volume (pooled MD, 62.19; 95% CI, 17.91–106.48; P < 0.05), BCI (pooled MD, 23.59; 95% CI, 8.15–39.04; P < 0.05), and PdetQmax (pooled MD, 28.62; 95% CI, 6.72–50.52; P < 0.05) were observed after surgery. In addition, after more than 1 year, significant improvements were observed in Qmax (pooled MD, 6.75; 95%CI, 4.35–9.15; P < 0.05), IPSS(pooled MD, − 13.76; 95%CI, − 15.17–12.35; P < 0.05), PVR (pooled MD, − 179.78; 95%CI, − 185.12–174.44; P < 0.05), QoL (pooled MD, − 2.61; 95%CI, − 3.12–2.09; P < 0.05), and PdetQmax (pooled MD, 27.94; 95%CI, 11.70–44.19; P < 0.05). Compared with DU patients who did not receive surgery, DU patients who received surgery showed better improvement in PVR (pooled MD, 137.00; 95%CI, 6.90–267.10; P < 0.05) and PdetQmax (pooled MD, − 8.00; 95%CI, − 14.68–1.32; P < 0.05). Conclusions Our meta-analysis results showed that transurethral surgery can improve the symptoms of BPH patients with DU. Surgery also showed advantages over pharmacological treatment for BPH patients with DU. Systematic review registration PROSPERO CRD42023415188.