BackgroundLactylation, a recently identified post-translational modification mediated by lactate, plays a critical role in regulating metabolic and immune processes in tumors. However, its function in neuroblastoma, particularly its association with tumor progression and immune modulation, remains unclear.MethodWe conducted immunohistochemical analyses on neuroblastoma tissue samples to evaluate lactylation levels and their clinical relevance. Single-cell RNA sequencing data and the AUCell algorithm were utilized to identify lactylation-related genes (LRGs) and map their expression within the tumor microenvironment. A seven-gene LRGs-based prognostic model was constructed using Cox regression and Least absolute shrinkage and selection operator (LASSO) analysis and validated in independent datasets. Bioinformatics analyses were performed to assess the associations between LRGs and clinical characteristics, biological pathways, immune infiltration, and therapeutic response. Functional assays further investigated the role of KLHL32, a key gene identified in the model.ResultsOur study revealed significantly elevated lactylation levels in neuroblastoma tumor tissues, which were associated with advanced disease stages and poor prognoses. We identified 407 LRGs and developed a seven-gene prognostic model that effectively stratified patients by risk, showing robust predictive performance in both internal and external validations. High-risk patients exhibited increased activation of tumor-promoting pathways, including glycolysis and PI3K/AKT signaling, alongside reduced immune cell infiltration, indicative of an immunosuppressive tumor microenvironment. Among the LRGs, KLHL32 emerged as a key tumor suppressor, inhibiting neuroblastoma cell proliferation, migration, and invasion, while enhancing NK cell-mediated cytotoxicity and anti-GD2 immunotherapies response. KLHL32 overexpression suppressed lactate production by downregulating the PI3K/AKT pathway, reducing protein lactylation levels, and promoting anti-tumor immunity.ConclusionOur findings establish lactylation as a critical determinant of neuroblastoma progression and prognosis. The seven-gene lactylation-related prognostic model provides a novel tool for patient stratification and therapeutic decision-making. Additionally, KLHL32 represents a promising target for enhancing immunotherapy efficacy by modulating metabolic and immune pathways, offering new opportunities for precision treatment in high-risk neuroblastoma patients.

Lactylation is a novel lysine acylation modification, and its function and exact mechanisms remain unclear. The responsiveness to combined targeted and immunotherapy continues to be a major challenge in cancer treatment. Here, we discovered that lysine lactylation (Kla) is specifically downregulated in targeted therapy-resistant renal cancer cells and tissues. The lactylation status of YAP at lysine 90 (K90) regulates its nuclear translocation, which is critical for the expression of epithelial-mesenchymal transition (EMT)-related genes and the PD-L1 gene. Furthermore, we identified HDAC1 as the “eraser” of YAP-K90 lactylation. By transfecting YAP-K90T (a lactylation mimic), we enhanced antitumor immune activity. In xenograft models established in huCD34+HSC NCG mice, we consistently found that HDAC1 inhibition enhances the response to combination therapy by increasing YAP lactylation and promoting CD8⁺ T cell tumor infiltration. These findings reveal lactylation as a key mechanism in targeted drug response and identify inhibiting YAP delactylation as a promising strategy for renal cell carcinoma treatment.

The progression and therapeutic response of clear cell renal cell carcinoma (ccRCC) are critically shaped by the complex interactions between tumor cell heterogeneity and the tumor immune microenvironment (TIME). However, a comprehensive classification of the ccRCC ecosystem and its clinical relevance is lacking. To address this, we utilized comprehensive bioinformatics approaches to analyze ten public single-cell RNA sequencing datasets from 194 samples across 118 ccRCC patients. Across 1,172,154 cells, we identified four TIME subtypes (immune activation, innate immunity, immunosuppressive myeloid [ISM], and immune exclusion) and six functional states of tumor cells (metabolic, angiogenic, stress-responsive, antigen-presenting, cell cycling, and epithelial-mesenchymal transition [EMT]). The interplay between these components defined four immune ecosystems, among which the ISM subtype, coupled with the EMT tumor state was associated with the poorest prognosis. Using machine learning-based prognostic modeling, we highlighted FKBP10 as a critical prognostic gene. Mechanistically, we demonstrated that FKBP10 not only promoted EMT but also activated the MEK/ERK/ELF3 signaling axis, leading to an increased secretion of CXCL8 by tumor cells. Tumor-derived CXCL8, in turn, drove macrophage M2 polarization and myeloid-derived suppressor cell (MDSC) recruitment, thereby reinforcing an immunosuppressive TIME. Furthermore, targeting FKBP10 synergized with anti-PD-1 therapy in suppressing tumor growth in vivo. Our work provides a comprehensive molecular atlas of the ccRCC ecosystem, establishes FKBP10 as a key regulator of immune suppression, and highlights its potential as a therapeutic target for personalized immunotherapy.

RATIONALE AND OBJECTIVES:Unresectable hepatocellular carcinoma (uHCC) remains a formidable clinical challenge owing to the scarcity of effective treatment options and unsatisfactory therapeutic responses. The current study explored a combined regimen of RALOX-HAIC, lenvatinib, and camrelizumab in patients with uHCC. In addition, a radiomics-based nomogram was created to predict treatment outcomes and support individualized decision-making. METHODS:A total of 98 patients with uHCC received RALOX-HAIC, along with lenvatinib and camrelizumab. Before initiating therapy, radiomics features were derived from pretreatment computed tomography (CT) images and subsequently integrated with clinical variables, such as HBV status and Child-Pugh score. A radiomics nomogram was generated and assessed based on the area under the receiver operating characteristic curve (AUC), calibration analysis, and decision curve analysis (DCA). RESULTS:Triple therapy yielded an objective response rate (ORR) of 52.0%, disease control rate (DCR) of 90.8%, and median progression-free survival (PFS) of 10.7 months (95% CI: 7.3-20.5). The radiomics-guided nomogram showed high accuracy in the training (AUC: 0.986) and validation (AUC: 0.873) sets. The calibration curves showed close agreement between the projected and observed outcomes, and DCA confirmed the notable clinical merit. The main grade ≥3 toxicities included neutropenia and thrombocytopenia (68.4%), consistent with the profiles observed in comparable therapies. CONCLUSION:The integrated approach exhibited promising antitumor activity and an acceptable safety profile. Moreover, the radiomics nomogram is a valuable tool for refining patient selection and advancing personalized treatment strategies for individuals with uHCC.

Androgen-activated phosphorylation signaling pathways are of critical importance during spermatogenesis. The present study comprehensively analyzed androgen-activated phosphorylation signaling pathways in testicular Sertoli cells. Primary cultured mouse Sertoli cells were treated with testosterone for varying durations. Using tandem mass tag-labeled phosphoproteomics technology combined with Mfuzz clustering and functional enrichment analysis, key phosphorylation signaling pathways were identified. Mass spectrometry revealed 13,015 quantifiable phosphorylation sites, and Mfuzz clustering of expression pattern categorized 330 proteins into 6 clusters. Functional enrichment analysis highlighted key pathways, including Rap1 and MAPK kinases. Inhibitor experiments confirmed that the disruption of phosphorylation signaling impaired the integrity of the blood-testis barrier. Collectively, these findings demonstrated that androgens rapidly activate the protein phosphorylation signaling network in Sertoli cells, regulating critical processes such as blood-testis barrier formation, thereby providing new insights into male fertility and potential therapeutic strategies for spermatogenic disorders.

Molecular characterization of non-muscle-invasive bladder cancer (NMIBC) provides critical insights into the heterogeneity of clinical outcomes and treatment responses. The integration of existing transcriptomic subtyping systems to reconcile inconsistencies would facilitate clinical translation. The Markov cluster algorithm was utilized to construct a network integrating five published bladder cancer classification systems based on transcriptional profiles, aiming to establish an integrated molecular classification framework and identify different prognostics clusters. Four integrated molecular clusters (IMC1-4) with distinct transcriptomic, genomic, proteomic and clinical characteristics were identified. IMC2 exhibited significant enrichment of FGFR3 mutations, whereas IMC4 showed predominant TP53 alterations. IMC1 and IMC3 demonstrated improved PFS following Bacillus Calmette–Guérin (BCG) instillation in patients recommended for BCG treatment per the European Association of Urology (EAU) guidelines. Using transcriptomic profiles, a single-sample classifier was developed to categorize tumors into integrated molecular clusters. This study provides an integrated classification system to understand the heterogeneity of NMIBC and establish a preclinical framework for clinical management, therapeutic targets, and monitoring of clinical trials.

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .

In this study, we systematically integrated proteome and acetyl proteome (acetylome) approaches to investigate the characteristics of renal proteins in a CaOx crystal rat model. We aimed to understand the pathogenesis of kidney calculi and delineate the landscape of acetylation within kidney calculi, potentially leading to the identification of valuable and novel biomarkers. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we analyzed the protein expression profiles and lysine acetylation (Kac) features in kidney tissues obtained from rats with kidney calculi and those without (normal controls). Our results revealed 118 downregulated and 129 upregulated proteins. Furthermore, we identified 538 upregulated Kac sites in 258 proteins and 133 downregulated Kac sites in 118 proteins between kidney calculi and paired normal rats. Functional enrichment and protein-protein interaction network analyses revealed that the mitochondria were the most abundant acetylated protein fraction, and metabolic pathways were predominated among the GO and KEGG pathways. Furthermore, the LC-MS/MS findings were verified by immunofluorescence. The study is the first comparative study of Kac modification associated with kidney calculi. These findings offer significant insights into the molecular mechanism underlying the formation and development of renal stones.

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is a common and aggressive form of kidney cancer with VHL mutations present in > 50% of cases. These mutations lead to dysregulation of hypoxia‐inducible factors (HIFs) and activation of oncogenic pathways, making VHL‐deficient ccRCC a challenging target for therapy. In this study, we identified cc‐885, a molecular glue degrader, as a selective inhibitor of VHL‐deficient ccRCC. cc‐885 promotes ubiquitination and degradation of transcription factor ETS1, which cooperates with EPAS1 (HIF‐2α) to drive tumorigenesis. We demonstrated that cc‐885 selectively targeted the p51 and p42 isoforms of ETS1, disrupting p27/p51 balance and suppressing ETS1 transcriptional activity. Moreover, combining cc‐885 with an EPAS1 inhibitor, belzutifan, significantly enhanced the anti‐tumor efficacy. Our findings provide a novel and precise therapeutic strategy for VHL‐deficient ccRCC by targeting ETS1 degradation and disrupting the ETS1‐EPAS1 complex.

Non-alcoholic fatty liver disease (NAFLD) ranks among the most common liver disorders, but the mechanisms underlying its early development are still not well understood. This study aims to compare the effects of varying degrees of lipid accumulation on autophagy and energy metabolism signaling pathways to further elucidate the early pathogenesis of NAFLD. Low-level and classical lipid accumulation models were generated in AML12 and HepG2 cells in vitro using various concentrations of oleic acid and palmitic acid. For in vivo models, Tyloxapol and high-fat diet were utilized to construct both low-level and classical lipid accumulation models. We used Western blot analysis to assess the phosphorylation status of peroxisome proliferator-activated receptor α (PPARα) and AMP-activated protein kinase (AMPK), as well as the expression levels of autophagy-related proteins. We found that low-level lipid accumulation models significantly promoted the expression of the lipid oxidation protein PPARα, and enhanced autophagy activity and AMPK phosphorylation. However, these positive effects were inhibited in classical lipid accumulation models. Our research identified a compensatory mechanism in the early stages of NAFLD. Appropriate lipid accumulation can increase the levels of fatty acid oxidation proteins and autophagy, potentially mediated by the energy metabolism regulator AMPK. This discovery offers additional theoretical insights into the onset and progression of early-stage NAFLD.

Kidney stone ranks as one of the most prevalent disorders in the urology department, causing substantial personal suffering and healthcare costs globally. However, the prediction, early diagnosis, and treatment of kidney stone disease are still limited. Extracellular vesicles (EVs), loaded with nucleic acids, proteins, metabolites, and lipids, are released by a wide variety of cell types and have potential as biomarkers for kidney stone disease. Meanwhile, some natural EVs derived from plants and animals have been evidenced to have substantial effects on the elimination of calcium oxalate crystals. More importantly, recent explorations have elucidated the multifaceted role of EVs in therapeutic applications. These engineered EVs can be loaded with therapeutic RNAs, oligonucleotides, peptides, and small molecules; this approach has shown great promise in targeted drug delivery and presents a potential solution to the challenges of kidney stone prevention and treatment. This review focuses on EVs derived from blood, urine, kidney, gut microbiota, and urine bacteria, which contribute to calcium oxalate crystal elimination. The therapeutic potential of EVs is significant, offering personalized treatment options. However, it is crucial to assess the challenges in moving EV‐based therapies from laboratory settings to clinical applications.

Polycystic ovary syndrome (PCOS) is one of the causes of endocrine disorders and infertility in women of childbearing age, which seriously affects women's health. The etiology of PCOS is still unknown, and metabolic abnormalities are the focus of current research. A large number of studies have shown that gut microbiota is related to metabolic abnormalities. This project intends to study the relationship between gut microbiota and PCOS and analyze the molecular mechanism of its impact on PCOS. The project is designed to conduct 16S rRNA sequencing and analysis using feces from patients with polycystic ovary syndrome. 48 samples were included in the study and divided into 3 groups (NOR, POS1, POS2), Venn diagram shows that there are 372 operational taxonomic units in total, and 96, 43 and 20 unique to the 3 groups respectively. PLS-DA analysis shows that there are significant differences among the 3 groups. Species abundance analysis shows that there are differences among the 3 groups at the level of class, family, genus, order, phylum and species. There are more lachnoanaerobcaulum and Klebsiella in POS1 group, and more enterococcaceae and enterococcu in POS2 group. The correlation analysis showed that Klebsiella and Lachnoanaerobaculum were positive associated with BMI, and LH level, respectively, and Enterococcus was negative correlated with the levels of LH and testosterone. This study can provide reference basis for clinical accurate and personalized dietary intervention and drug treatment of PCOS.

Background: Natural killer cells, interconnected with patient prognosis and treatment response, play a pivotal role in the tumor immune microenvironment and may serve as potential novel predictive biomarkers for renal cell carcinoma. Methods: Clear cell renal cell carcinoma transcriptome data and the corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) database. Single-cell sequencing data were sourced from the Gene Expression Omnibus (GEO) database. A risk model was established by integrating ten different machine learning algorithms, which resulted in 101 combined models. The model with the highest average C-index was selected for further analysis, and was assessed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan-Meier survival analysis. The differences in immune infiltration fractions, clinicopathological features, and response to various targeted therapies and immunotherapy between high- and low-risk groups were investigated. Furthermore, qRT-PCR, IHC, colony formation test, CCK8 assay and flow cytometry were conducted to explore the expression pattern and function of ARHGAP9 in our own patient samples and renal cancer cell lines. Results: Totally, 156 NK cell-related genes and 5189 prognosis-related genes were identified, and 36 genes of their intersection demonstrated prognostic value. A risk model with 18 genes was established by Coxboost plus plsRcox, which can accurately predict the prognosis of ccRCC patients. Significant correlations were determined between risk score and tumor malignancy and immune cell infiltration. Meanwhile, a combination of tumor mutation burden plus risk score could have higher accuracy of predicting clinical outcomes. Moreover, high-risk group patients were more likely to be responsive to targeted therapy but show no response to immunotherapy. Conclusions: Intricate signaling interactions between NK cells and various cellular subgroups were depicted and the developmental trajectory of NK cells was elucidated. A NK cells-related risk model was established, which can provide reliable prognostic information and identified patients with more probability of benefiting from therapy.

In order to explore efficient ATP-competitive mTOR inhibitors and aid the development of targeted anticancer drugs, this study focuses on virtual screening and molecular dynamics simulations. The compounds were sourced from the ChemDiv commercial compound library, and through virtual screening, 50 ligands with favorable binding modes and excellent docking scores were selected from 902,998 compounds. Molecular dynamics simulations, including RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation), were used to further evaluate these 50 ligands. Structural stability, key residue interactions, hydrogen bonding, binding free energy, and other factors were quantitatively and qualitatively analyzed. Top1, top2, and top6, which exhibited outstanding performance, were identified. Simulations revealed that they bind stably in the active region of the mTOR protein, forming hydrogen bonds, π-π interactions, and hydrophobic interactions with key amino acid residues such as VAL-2240 and TRP-2239. This study provides a solid theoretical foundation for the development of mTOR inhibitors. Subsequent efforts will focus on optimizing these compounds, targeting structural adjustments to enhance their biological activity and specificity towards mTOR, thereby achieving more precise targeting and treatment of tumors.

IntroductionThe gastrointestinal tract is the organ most extensively distributed by autonomic nerves, and researches have indicated a relationship between automatic nerves and the progression of gastrointestinal cancers. This study aimed to evaluate the autonomic nervous function in patients with gastrointestinal cancer and to explore its relationship with clinical characteristics.MethodsWe employed the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire and cardiovascular autonomic reflex tests (CARTs) to evaluate autonomic nervous function, while also conducting a thorough analysis of clinical data.ResultsOur results showed that low white blood cell (WBC) count (OR = 0.461, 95% CI: 0.218–0.976, p = 0.043) and increased maximum tumor diameter (OR = 1.619, 95% CI: 1.025–2.555, p = 0.039) were risk factors for autonomic dysfunction according to the COMPASS-31 assessment. While hypertension (OR = 5.747, 95% CI: 1.186–27.862, p = 0.030) and elevated platelet-to-albumin ratio (PAR) (OR = 1.256, 95% CI: 1.025–1.540, p = 0.028) were identified as independent risk factors for autonomic dysfunction based on the CARTs results. Combining the findings from COMPASS-31 and CARTs revealed that older age (OR = 1.133, 95% CI: 1.015–1.264, p = 0.027) and vascular invasion (OR = 7.706, 95% CI: 1.391–42.684, p = 0.019) were also independent risk factors for autonomic dysfunction.ConclusionOur findings reveal that these specific factors related to gastrointestinal cancers significantly influence autonomic nervous function. It is essential to evaluate autonomic nervous function and its associated risk factors in patients with gastrointestinal malignancies, which provide new insights into the intervention strategies for cancer diseases.

BackgroundExisting studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated.MethodsPatient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing.ResultsCircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor.ConclusionA novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

PURPOSE:Chromosome 7 open reading frame 61 (C7orf 61) was a testis-specific gene, and may be involved in the process of spermatogenesis. This study aimed to investigate the expression of C7orf61 in the testis and determine its role in spermatogenesis. MATERIALS AND METHODS:Reverse transcription-quantitative polymerase chain reaction, Western blot and immunofluorescence were performed to evaluate the expression characteristics of C7orf61 in mice and humans. In vitro fertilization assay was used to determine the role of the C7ORF61 protein in sperm-egg fusion. RESULTS:The results demonstrated that C7orf61 was a testis-specific gene; the C7ofr61 mRNA expression level sharply increased in the fourth postnatal week and gradually increased until the adult stage. The C7ORF61 protein was located throughout the subacrosomal area and close to the nucleus in both mouse and human sperm. The incubation with the C7ORF61 antibody significantly decreased the fertilization rate of mouse eggs. CONCLUSION:The present findings suggested that the C7ORF61 protein might be involved in sperm-egg fusion, and could serve as a useful target for contraceptives. However, further research is still needed to know the detailed molecularmechanismofitsrole.

Background TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. Methods Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. Results The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. Conclusions TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

Kidney stone disease (KSD) is a major public health concern associated with high morbidity and recurrence, places a significant burden on the health care system worldwide. Calcium oxalate (CaOx) alone or a mixture of CaOx and calcium phosphate stones accounting for more than 80 % of cases. However, beyond surgical removal, the prevention and reduction of recurrence of CaOx kidney stones have always been a challenge. Given that macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis, which have gained more and more interests in nephrolithiasis. Several studies recently clearly demonstrated that M2-macrophage could reduce the renal calcium oxalate (CaOx) crystal acumination, and provide premise insights and therapeutic options for KSD by modulating the macrophage phenotypes. However, the mechanism of macrophage-polarization regulation and that effects on kidney stone prevention and treatments are far from clear. Here, we comprehensively reviewed the literatures related to cytokines, epigenetic modifications and metabolic reprograming of macrophage in CaOx kidney stone disease, aimed to provide better understandings on macrophage polarization regulation as well as its potential clinical applications in CaOx kidney stone disease treatments and prevention.

The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.