INTRODUCTION:Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women, characterized by hyperandrogenism and metabolic dysfunction. Dietary interventions are recommended as one of the first-line therapies. Oligofructose (OFS), a prebiotic fiber, has demonstrated clinical benefits in PCOS; however, its underlying mechanism remains unclear. OBJECTIVES:To determine whether OFS alleviates PCOS-like phenotypes through bile acid-dependent mechanisms and to identify downstream ovarian steroidogenic responses. METHODS:Letrozole-induced PCOS-like mice received OFS supplementation. Microbiota dependence was assessed using antibiotic depletion and fecal microbiota transplantation. Bile acid involvement was evaluated using cholestyramine. Gut microbial composition and function were profiled by 16S rRNA and metagenomic sequencing, and bile acids were quantified by UHPLC-MS/MS. Ovarian transcriptomics, ex vivo ovarian explants, and primary granulosa cells were used to examine steroidogenic changes, with pharmacological inhibition applied to assess TGR5-related signaling. RESULTS:OFS improved reproductive and metabolic abnormalities in PCOS-like mice. These benefits were abolished by microbiota depletion and bile acid sequestration, indicating microbiota- and bile acid-dependent effects. OFS was associated with increased circulating hyodeoxycholic acid (HDCA), which negatively correlated with serum testosterone. HDCA supplementation partially reproduced endocrine improvements under microbiota-depleted conditions. Ovarian transcriptomic and functional analyses demonstrated enhanced aromatization following OFS treatment. In ex vivo ovarian explants and primary granulosa cells, HDCA increased estradiol production, reduced testosterone, and upregulated CYP19A1 (encoding aromatase). Under androgen stimulation, pharmacological inhibition of TGR5 attenuated HDCA-associated increases in estradiol and aromatase activity, supporting involvement of TGR5-related signaling. CONCLUSION:OFS alleviates PCOS-like phenotypes in a microbiota- and bile acid-dependent manner and enhances ovarian aromatization. These findings move beyond descriptive bile acid alterations in PCOS by providing functional evidence that dietary fiber-induced bile acid remodeling is associated with modulation of ovarian steroidogenic regulation.

Nasopharyngeal carcinoma (NPC) is a type of cancer that is prevalent in southern China. In the development of NPC, the oncogenic protein LMP1, which is encoded by EBV, plays a very important role. The Wnt pathway is abnormally activated in many types of malignant tumors. The interaction between AXIN and DVL2 is pivotal for the breakdown of the β-catenin destruction complex and Wnt/β-catenin pathway activation. However, the molecular mechanisms underlying this process in NPC are not well understood. In this study, we identified the transmembrane protein LMP1 as an interacting partner of DVL2, which positively regulates the Wnt/β-catenin pathway by inhibiting the AXIN-DVL2 interaction. LMP1 overexpression enhanced NPC cell growth, metastasis, and stemness, whereas LMP1 knockdown suppressed these abilities. Our findings reveal new oncogenic roles for LMP1 in NPC progression.

BACKGROUND & AIMS:Patients with liver cirrhosis exhibit increased susceptibility to bacterial infections; however, the specific immune defects facilitating this vulnerability remain incompletely understood. We aimed to characterize the dysregulated intercellular crosstalk within the cirrhotic liver that compromises antibacterial defense. METHODS:We performed single-cell RNA sequencing (scRNA-seq) on livers from control and cirrhotic mice with or without bacterial infection. Inferred cellular interactions were validated using flow cytometry, targeted metabolomics, and functional assays, including ex vivo co-culture, in vivo adoptive transfer, antibody blockade, and transgenic mouse models. Clinical relevance and mechanistic conservation were established utilizing human bulk and single-cell transcriptomic datasets from GEO, alongside validation in a nationwide multicenter prospective clinical cohort (CATCH-LIFE). RESULTS:scRNA-seq and functional assays revealed a significantly depleted CD44+ plasmacytoid dendritic cells (pDCs) subpopulation responsible for impaired antibacterial immunity in cirrhosis. Mechanistically, CD44+pDCs do not kill bacteria directly; rather, they sense pathogens via TLR7/9 to secrete type I IFN-α, which subsequently stimulates macrophage chemotaxis, reactive oxygen species (ROS) production, and bacterial phagocytosis. The hepatic recruitment of CD44+pDCs is governed by the CCL5-CCR5 axis, orchestrated by a specific subset of CCL5-associated hepatocytes (marked by Mup11 in mice). Targeted metabolomics identified that anserine, a histidine metabolite depleted in cirrhosis, intrinsically upregulates hepatocyte CCL5 expression. Anserine supplementation successfully restored the hepatocyte-pDC protective axis, significantly reducing bacterial burden and mortality in cirrhotic mice. Finally, multi-omics human data and the CATCH-LIFE cohort demonstrated that levels of CCL5, anserine, and CD44+ pDCs were significantly correlated with infection incidence and clinical outcomes in patients with cirrhosis. CONCLUSION:We uncover a novel anserine-CCL5-pDC-macrophage metabolic-immune axis that is critically impaired in cirrhosis. Restoring this network offers a promising predictive and therapeutic strategy for cirrhosis-associated infections. IMPACT AND IMPLICATIONS:Patients with cirrhosis face a critically high risk of bacterial infections, yet the specific immune defects driving this susceptibility have remained elusive. This study uncovers a novel metabolic-immune mechanism wherein the histamine metabolite anserine potentiates a protective crosstalk between hepatocytes and CD44+ plasmacytoid dendritic cells (pDCs). We demonstrate that this axis relies on conserved CCL5-CCR5 signaling to recruit pDCs, which subsequently orchestrate bacterial clearance via TLR7/9-mediated IFN-α secretion and macrophage activation. Importantly, these findings were validated in a multi-center prospective human cohort, showing that anserine, CCL5 and CD44+ pDCs levels significantly correlate with infection incidence and clinical outcome. This uncovers a previously unrecognized metabolic-immune vulnerability in cirrhosis and suggests that anserine supplementation or targeting the CCL5-pDC axis could serve as a precision therapy to decrease infection-related mortality in cirrhosis.

Drug resistance remains a major challenge in cancer therapy and limits the efficacy of chemotherapy, targeted therapy, and immunotherapy. Recent studies highlight RNA epitranscriptomic regulation, especially N4-acetylcytidine (ac4C), as an important mechanism in tumor adaptation. NAT10, the main enzyme that catalyzes ac4C formation, regulates RNA stability and translation. It plays key roles in cancer stemness, DNA repair, metabolic reprogramming, EMT, and immune regulation. Therefore, NAT10 has emerged as an important regulator of drug resistance in multiple cancer types. Mechanistically, NAT10 stabilizes key transcripts involved in DNA damage repair, metabolism, stemness, and EMT, thereby promoting tumor cell survival. It also enhances DNA repair by regulating DNA:RNA hybrid stability and homologous recombination, which reduces the effectiveness of DNA-damaging therapies. As a result, NAT10 contributes to resistance against cisplatin and other platinum drugs, doxorubicin, EGFR-TKIs, PARP inhibitors, and sorafenib. These resistance programs converge on a shared adaptive network involving DNA repair activation, metabolic rewiring, stemness maintenance, and immune escape. Remodelin is a small-molecule inhibitor of NAT10. It blocks ac4C modification and reverses drug resistance through multiple mechanisms. These include inhibition of DNA repair, suppression of metabolic adaptation, reversal of EMT, and improvement of the immune microenvironment. In preclinical models, Remodelin enhances the efficacy of chemotherapy, targeted therapy, and immunotherapy. However, clinical translation remains limited by issues such as off-target effects, toxicity, mechanistic complexity, and feedback regulation. Future work should focus on developing more selective NAT10 inhibitors, optimizing combination therapies, and identifying predictive biomarkers. Overall, NAT10 represents a potentially actionable regulator of cancer therapy resistance in selected tumor contexts, while Remodelin remains a useful preclinical tool for exploring NAT10-targeted strategies. Further validation is required before NAT10 inhibition can be considered a clinically applicable approach.

The tumour immune microenvironment (TIME) can be considered a dynamic ecosystem, which requires rapid proteomic adaptation for immune evasion. While transcriptional control is undoubtedly significant, post-transcriptional mechanisms, most notably translational regulation, facilitate immediate proteome rewiring. Cold Shock Domain Containing E1 (CSDE1), an RNA-binding protein, has emerged as a pivotal upstream regulator of translational control, orchestrating multiple facets of mRNA metabolism, including translation initiation, elongation, and stability. While its context-dependent roles in tumourigenesis are recognised, the function of CSDE1 in immune regulation remains incompletely understood. This review synthesises emerging evidence to position CSDE1 as a central architect of immunosuppression through spatiotemporal translational reprogramming. The present study delineates the manner in which CSDE1 facilitates tumour-intrinsic immune evasion by suppressing antigen presentation and neutralising immunogenic signalling (e.g. cGAS-STING), while concurrently dictating the fates of immune cells – ranging from the development of haematopoietic stem cells to the differentiation of T and B cells. These findings are integrated to propose a novel conceptual framework of spatiotemporal translational reprogramming. This framework posits that CSDE1 decodes the cellular context to dynamically configure translational output across temporal (tumour initiation, progression, therapy resistance) and spatial (cytoplasm, nucleoplasmic reticulum, stress granules, immunological synapse) dimensions. Finally, we explore the therapeutic targeting of CSDE1 through combinatory genotoxic therapy, neoantigen vaccines, immunotherapy sensitisation, and physical stimulation, proposing CSDE1 as a novel therapeutic nexus to overcome resistance in tumour immunotherapy. CSDE1 has been identified as a central context-decoder and a promising therapeutic nexus in the TIME. However, its duality and essential physiological roles pose significant translational challenges.

Targeted therapy has emerged as a promising precision medicine strategy for immunoglobulin A nephropathy (IgAN) through the modulation of specific pathogenic pathways. Although research in this area has accelerated, the literature remains scattered, and no bibliometric study has mapped its global knowledge structure or evolving hotspots. We conducted a bibliometric and visualization analysis of 678 publications indexed in the Web of Science Core Collection (1999–2025). CiteSpace 6.4R1, VOSviewer 1.6.20, and the R‑based bibliometric package were used to assess publication and citation trends; identify prolific countries, institutions, authors, and journals; and generate co‑authorship, co‑citation, and keyword co‑occurrence networks. Research frontiers were explored through thematic evolution mapping and keyword burst detection. Annual publications increased notably after 2015, indicating a shift from supportive care to molecularly targeted interventions. China and the United States produce over 60

Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes in gastrointestinal stromal tumors (GIST), but acquired resistance remains a major clinical obstacle. The underlying mechanisms that sustain oncogenic KIT signaling in TKI-refractory GIST are not fully understood. Here, we identify a previously unrecognized epigenetic–epitranscriptomic regulatory axis involving SETD2, FTO, and KIT that promotes TKI resistance by stabilizing KIT mRNA. FTO, a key N6-methyladenosine (m6A) RNA demethylase, was found to be markedly overexpressed in high-risk and recurrent GIST samples and correlated with poor prognosis. Mechanistically, FTO enhances KIT mRNA stability by erasing m6A modification in its 3′ untranslated region (UTR), thereby preventing YTHDF2-mediated degradation and sustaining oncogenic KIT expression. Furthermore, the histone methyltransferase SETD2 activates FTO transcription via H3K36 trimethylation at the FTO promoter, establishing a self-reinforcing loop that maintains FTO overexpression. Functional experiments using FTO knockout and pharmacological inhibition (CS1 and entacapone) demonstrated that disrupting FTO activity suppresses tumor proliferation, reduces KIT expression, and restores sensitivity to imatinib both in vitro and in vivo. In KIT-Asp818Tyr/+ genetically engineered GIST mouse models, the combination of entacapone and imatinib led to significant tumor regression. Most importantly, preliminary clinical results from a Phase I trial (ClinicalTrials.gov: NCT04006769) showed that treatment with entacapone plus imatinib resulted in partial remission in two out of three evaluable TKI-refractory GIST patients, supporting the translational relevance of this strategy. Collectively, our findings establish the SETD2–FTO–KIT axis as a critical mechanism driving drug resistance in GIST and reveal m6A demethylation as a key regulator of KIT mRNA stability. Targeting FTO represents a promising and actionable therapeutic strategy to overcome TKI resistance and improve outcomes for patients with advanced GIST.

TP53 is frequently mutated in bladder cancer and is associated with aggressive disease, yet actionable strategies that also improve responses to immune checkpoint blockade remain limited. Here we show that APR-246 (eprenetapopt), a mutant p53–reactivating agent, preferentially reduces viability in TP53-mutant bladder cancer cell lines and that its activity appears to be partially dependent on mutant p53. Mechanistically, APR-246 induces pronounced reactive oxygen species accumulation and engages ferroptosis and apoptosis in parallel, accompanied by reactivation of p53-associated transcriptional programmes. RNA sequencing and orthogonal validation further reveal increased expression and secretion of the T cell–recruiting chemokines CCL5 and CXCL10. In syngeneic subcutaneous and orthotopic bladder tumour models, APR-246 suppresses tumour growth and is associated with increased infiltration of CD8⁺ and CD4⁺ T cells and natural killer cells, though limited by sample size in animal models; This antitumour effect is attenuated in immunodeficient hosts. Notably, APR-246 augments the efficacy of anti–PD-1 therapy and further enriches effector immune infiltration. Together, these findings link mutant p53 targeting and redox-driven cell death to immune remodelling, providing a mechanistic rationale for combining APR-246 with PD-1 blockade in bladder cancer.

Tumor cells display profound changes in the metabolism of branched-chain amino acids (BCAA). However, how these changes are regulated to facilitate tumorigenesis is not yet completely understood. Here, we identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a BCAA-responsive protein through extensive screening using stable isotope labeling with amino acids in cell culture (SILAC). PPDPF is upregulated in cholangiocarcinoma to enhance the malignant phenotype of cholangiocarcinoma cells by activating the mTORC1 signaling pathway. Metabolic flux analysis and mechanistic studies revealed that PPDPF prevented the interaction between MCCA and MCCB, thus inhibiting leucine catabolism and activating mTORC1 signaling. Moreover, upon amino acid starvation, ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) and OTU deubiquitinase 4 (OTUD4) cooperatively regulated the stability of the PPDPF protein by modulating its ubiquitination. Additionally, monocytes/macrophage-derived IL-10 increased the BCAA content in cholangiocarcinoma cells and stabilized the PPDPF protein, even under amino acid starvation conditions. Knockout of PPDPF or restriction of leucine intake significantly inhibits the progression of cholangiocarcinoma in a mouse model. Collectively, we discovered a novel role for PPDPF in promoting the progression of cholangiocarcinoma by activating mTORC1 signaling through the inhibition of leucine catabolism. The present study suggests that targeting PPDPF or decreasing dietary leucine intake may provide a new strategy to improve the treatment efficacy of cholangiocarcinoma.

Background:Rheumatoid arthritis is a chronic autoimmune disease influenced by environmental exposures, including per- and polyfluoroalkyl substances (PFAS). Although previous studies have suggested links between PFAS and rheumatoid arthritis risk, none have used interpretable machine learning models for prediction. This study aimed to develop such a model to assess risk based on PFAS exposure. Methods:We analyzed data from 11,705 participants in the National Health and Nutrition Examination Survey (2003-2018). Twelve machine learning algorithms were evaluated using metrics including area under the curve (AUC), accuracy, sensitivity, specificity, and F1 score. Key predictors were identified using SHapley Additive exPlanations (SHAP). Partial dependence plots and locally weighted scatterplot smoothing (LOWESS) curves were used to examine non-linear associations and exposure thresholds. A web-based risk calculator was developed to enhance clinical and public health applicability. Results:CatBoost showed the best performance (AUC: 0.82; Accuracy: 74%; F1 score: 0.62) and was selected for further interpretation. SHAP analysis identified perfluorooctane sulfonic acid (PFOS) and 2-(N-Methyl-perfluorooctane sulfonamido) acetic acid (MPAH) as major contributors to risk prediction. PFOS exhibited a U-shaped relationship with increased risk above 15.10 ng/ml, while MPAH showed a risk transition at 0.22 ng/ml. Waterfall plots illustrated the contribution of individual exposures. The interactive web-based calculator allows users to input PFAS levels and receive personalized rheumatoid arthritis risk estimates. It is freely available on Hugging Face Spaces (https://huggingface.co/spaces/Machine199710/RA_ML). Conclusions:This study demonstrates the potential of machine learning to predict rheumatoid arthritis risk based on PFAS exposure. The identified non-linear patterns provide insights into environmental contributions to disease risk and may inform future prevention strategies.

Although docetaxel (DTX) is a first-line chemotherapeutic agent for treating prostate cancer (PCa), its clinical effectiveness is hampered by patients developing resistance following long-term, high-dose use. Additionally, its low bioavailability and significant toxicity further restrict its therapeutic potential. To address these issues, we developed hyaluronan (HA)-modified Prussian blue nanoparticles (PB NPs) that co-load DTX and chitosan-encased silver nanoparticles (Chi-Ag NPs), aimed at enhancing solubility, targeting capability, and therapeutic efficacy. In vitro assays demonstrated that HA-Ag-PB@DTX NPs could synergistically kill PC-3 cells by effectively targeting tumor cells and inducing cell apoptosis. In vivo studies showed that HA-Ag-PB@DTX NPs significantly inhibited tumor growth in heterotopic tumor-bearing mice through enhanced penetrability in tumor tissues and synergistic effects. Furthermore, these NPs markedly reduced the toxicity of DTX due to their controlled release and targeted delivery mechanisms. In conclusion, we have successfully developed novel nanocomplexes that improve the dosage of DTX and provide a synergistic approach for PCa therapy.

OBJECTIVE:The frequency of pathogenic variants (PVs) in HRAS in Caucasian populations with pheochromocytoma and paraganglioma (PPGL) is significantly lower than that in Chinese, which reflects the ethnic difference in genetic landscape. However, the clinical and biochemical characteristics of patients with HRAS-mutant PPGL are rarely reported. This study explored the clinical and biochemical profiles of Chinese patients with HRAS-mutant PPGL. DESIGN:This is a retrospective analysis of clinical and biochemical characteristics of patients with PPGL (N = 717). METHODS:Data on demographics, tumor characteristics, blood/urine biochemistry, preoperative preparation, intraoperative hemodynamics, and perioperative complications were analyzed in patients with HRAS-mutant and non-HRAS PPGL. RESULTS:A total of 111 (15.5%) patients were with PPGL due to PVs in HRAS. Patients with HRAS-mutant PPGL had higher plasma metanephrine levels, an increased incidence of catecholamine-associated signs and symptoms (CAS), intraoperative hemodynamic instability (IHI) and intensive care unit (ICU) transfer right after surgery compared with those with non-HRAS tumor. Despite with similar tumor size, patients with HRAS-mutant PPGL had significantly higher plasma metanephrine levels, a higher incidence of presenting CAS and IHI than those with tumors due to PVs in other genes associated with kinase pathways. A significantly high catecholamine content in HRAS-mutant PPGL was associated with high levels of enzymes of catecholamine metabolism such as tyrosine hydroxylase and phenylethanolamine N-methyltransferase, which was independent of tumor locations. CONCLUSIONS:Patients with HRAS-mutant PPGL have higher plasma metanephrine levels and a higher risk of IHI and ICU transfer, which therefore requires personalized perioperative managements.

Sepsis-associated acute kidney injury (S-AKI) is a critical and life-threatening clinical syndrome characterized by intricate pathophysiological mechanisms and lack of effective therapeutic strategies. Our previous investigations in a diabetic nephropathy model indicated the potential protective effect of the Vitamin D Receptor (VDR) in regulating autophagy. Nevertheless, the precise association and involvement regarding VDR and autophagy in sepsis-associated AKI remains unknown. This research aims to investigate the protective role and underlying mechanisms of VDR in mitigating S-AKI. Through establishment of S-AKI models in VDR knockout mice and treatment with vitamin D receptor agonist paricalcitol, we reported that VDR deficiency exacerbated renal functional deterioration and histological alterations induced by lipopolysaccharide, whereas VDR activation markedly ameliorated these impairments. Mechanistic inquiries revealed that VDR could restore the expression of ATG16L1, a key regulator in autophagosome formation, by inhibition of miR-20a-5p, thereby fostering autophago-some maturation and facilitating autophagic flux impaired by LPS in renal tubular epithelial cells. Moreover, luciferase and ChIP experiments corroborated the direct transcriptional regulation role of VDR on miR-20a-5p. Collectively, this investigation illuminates a novel pathway through which VDR regulate autophagic dysfunction induced by lipopolysaccharide via the VDR-miR20a-5p-ATG16L1 axis, thereby introducing a promising therapeutic target against sS-AKI.

Sepsis-associated acute kidney injury (SA-AKI) is a severe clinical condition with a high mortality. Currently, there is no specific therapy for SA-AKI, and clinicians can only rely on extensive supportive treatment. Therefore, finding effective methods for SA-AKI therapy is crucial to delay the progression of sepsis. Our previous studies have found that paricalcitol, an active vitamin D analog, can reduce renal inflammation and delay the progression of SA-AKI. However, expression inhibition of megalin caused by endotoxins can reduce the entry of active vitamin D into renal tubular epithelial cells and weakening its renal protective efficacy. Therefore, how to enhance the enrichment of paricalcitol in the kidney is a challenge. In this study, we constructed a nanodrug delivery system to enhance the enrichment of paricalcitol in the kidney by encapsulating paricalcitol into a poly lactic-co-glycolic acid (PLGA) nanosystem, forming PLGA@paricalcitol nanoparticles (PLGA@pari NPs). In vivo experiments demonstrated that PLGA@pari NPs exhibited higher accumulation in the kidneys and significantly improve renal function in septic mice. The study indicates that PLGA@pari NPs represent a simple, safe, and efficient drug delivery system that enhances the therapeutic efficacy for SA-AKI by improving renal accumulation. This study provides new insights for clinical treatment of SA-AKI.

Sepsis is a life-threatening clinical syndrome, and renal impairment associated with sepsis significantly increases patient mortality. Blood purification techniques are crucial in managing sepsis by removing inflammatory mediators and toxic substances from the bloodstream, thereby improving outcomes. Traditional modalities, including continuous renal replacement therapy, hemodialysis, and hemoperfusion, have demonstrated clinical efficacy in this context. Recent advancements in blood purification filters have enhanced sepsis treatment strategies. This review assesses the mechanisms and clinical applications of novel filters such as the oXiris filter, AN69ST membrane, CytoSorb, Hemopurifier, and others, focusing on their effectiveness in eliminating toxins and inflammatory mediators. The oXiris filter has demonstrated superior capacity to remove small molecular toxins, pro-inflammatory cytokines, and endotoxins while promoting renal protection and enhancing microcirculation. In contrast, the AN69ST membrane and CytoSorb filters have shown promising efficacy in cytokine clearance, though their ability to remove endotoxins is limited. The Hemopurifier specifically targets endotoxins like lipopolysaccharides, effectively suppressing inflammatory responses and mitigating renal damage. Furthermore, the integration of Extracorporeal Carbon Dioxide Removal (ECCO2R) with continuous renal replacement therapy (CRRT) offers benefits, including the regulation of carbon dioxide levels, maintenance of acid-base balance, and enhanced clearance of inflammatory factors from circulation. Additionally, selective removal of lipopolysaccharides (LPS) can alleviate leukopenia and immune dysregulation, preserving renal function. This review aims to provide clinical guidance for optimizing individualized treatment protocols to enhance survival rates and improve the quality of life for patients with sepsis-related AKI. Incorporating these advanced filtration technologies into routine clinical practice can transform sepsis management and pave the way for innovative therapeutic strategies in critical care.

Chronic kidney disease (CKD) progression is tightly associated with renal fibrosis, which is regulated by macrophage M2 polarization. The intestinal metabolite trimethylamine N-oxide (TMAO) has been reported to promote CKD, yet its underlying mechanism remains unclear. Here, we elucidated a mechanism wherein TMAO excreted through the kidneys alters the pyruvate metabolism of renal tubular epithelial cells, resulting in the production of lactic acid. Local lactic acid accumulation in the kidney promotes adjacent macrophage M2 polarization, a process speculated to be mediated by specific lactylation of macrophage genes. Through lactylation omics analysis, we identified histone H4 lysine 12 (H4K12) as the most significantly up-regulated lysine residue subjected to lactylation. Subsequent chromatin immunoprecipitation sequencing (ChIP-seq) assays revealed H4K12 lactylation on several glycometabolism gene promoters and genes. Furthermore, we found that this lactylation-mediated epigenetic regulation requires the assistance of the “porter”protein p300, as knockdown of p300 weakened the trend towards M2 polarization induced by lactic acid. Using an in vivo unilateral ureteral obstruction (UUO) mouse model, we verified the M2 polarization effect of TMAO and its detrimental role in CKD, as well as the protective effect of the TMAO inhibitor iodomethylcholine (IMC) on CKD. Clinical data validated the up-regulated TMAO’s effect on renal M2 polarization and fibrosis. Our findings suggest that CKD patients exhibit increased TMAO levels, which modulate the production of lactic acid by renal intrinsic cells. Epigenetic regulations mediated by lactic acid, particularly H4K12la on macrophage genes involved in glycometabolism, may contribute to M2 polarization. Targeting TMAO or its downstream pathways could have potential therapeutic benefits in CKD.

Introduction:Lautropia mirabilis is a rare cause of peritonitis associated with peritoneal dialysis-associated peritonitis (PDAP). We report the first documented case of PDAP caused by coinfection with L. mirabilis, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Case Presentation:A 67-year-old woman with end-stage renal disease secondary to polycystic kidney disease, on continuous ambulatory peritoneal dialysis for 3 years, developed PDAP. Initial peritoneal dialysis effluent (PDE) culture grew Streptococcus salivarius, and symptoms resolved with treatment. However, she was readmitted 2 days later with recurrent PDAP. Despite 18 days of empirical antibiotic therapy and repeated negative PDE cultures, the patient's symptoms persisted. Upon her transfer to our hospital, PDE white blood cell (WBC) count was 110 × 106/L. Targeted next-generation sequencing (tNGS) of the PDE performed on day one detected L. mirabilis (16,929 reads), CMV (944 reads), and EBV (285 reads). Therapy with intravenous moxifloxacin, intraperitoneal gentamicin, and oral ganciclovir led to rapid WBC decline and clinical improvement within 48 h. After 1 week of inpatient monitoring, the patient was discharged with a 2-week course of oral moxifloxacin. At the 2-week follow-up, the patient was asymptomatic with normal PDE WBC counts. Conclusion:Conventional culture methods may fail to detect uncommon pathogens, such as L. mirabilis. Culture-negative PDAP often necessitates empirical antibiotic therapy, carrying a high risk of failure and increased healthcare costs. This case suggests that tNGS could be used as a complementary diagnostic tool in selected cases of refractory, culture-negative PDAP, potentially aiding the identification of pathogens and guiding therapy.