Sodium-glucose cotransporter 2 (SGLT2) inhibitors have transformed the therapeutic landscape of type 2 diabetes by promoting glycosuria through inhibition of renal glucose reabsorption. Beyond glycemic control, accumulating evidence supports a spectrum of extraglycemic effects, with the strongest clinical evidence for cardiorenal protection and less established evidence for neurocognitive and anticancer applications. In this review, we examine the canonical renal mechanism, compound-specific structural and pharmacological differences, and emerging non-canonical pathways that may operate partly independently of glucose lowering. Particular attention is given to ion handling, mitochondrial function, metabolic remodeling, and inflammatory signaling, while distinguishing experimentally proposed transporter-independent actions from clinically validated effects. Integrative transcriptomic, proteomic, and metabolomic studies are discussed as hypothesis-generating approaches that can prioritize pathways and biomarkers but do not by themselves establish direct binding or causal efficacy. We further consider current clinical guideline positioning, safety and tolerability, non-diabetic applications, and the limitations that constrain translation from preclinical findings. By synthesizing mechanistic, clinical, and systems-level evidence, this review provides a balanced framework for evaluating the expanding therapeutic utility of SGLT2 inhibitors.

Background: Obesity-related glomerulopathy is increasingly common, yet its pathogenesis remains poorly understood. This study aimed to elucidate the mechanisms by which nonspecific glomerular IgG deposition promotes podocyte senescence in obesity-related glomerulopathy, thereby expanding potential therapeutic options. Methods: Kidney samples from patients with obesity-related glomerulopathy and diet-induced obese mice were used to compare glomerular IgG localization and abundance in obese versus control states. Causality between glomerular IgG accumulation and podocyte senescence was assessed by exogenous IgG supplementation and B cell deficiency mice. Primary podocytes were IgG-stimulated for transcriptomic and lipidomic profiling, and sphingomyelin phosphodiesterase 3 (Smpd3) was validated by in vitro and in vivo loss-of-function studies. Macrophage-specific FcRn deletion and anti-CD20 therapy were further used to evaluate IgG-targeted strategies for mitigating podocyte senescence and injury in ORG. Results: Glomerular IgG deposition was markedly increased in both patients with obesity-related glomerulopathy and mice with diet-induced obesity. Exogenous IgG supplementation in non-obese mice reproduced the glomerular IgG accumulation and podocyte senescence observed in HFD fed mice. Conversely, B-cell null diet-induced obese mice and anti-CD20 treated diet-induced obese mice showed greatly reduced glomerular IgG levels and attenuated podocyte injury. Mechanistically, IgG exposure activated podocyte sphingolipid metabolism, notably upregulating Smpd3 and increasing intra-podocyte ceramide. In vitro and in vivo Smpd3 knockdown prevented IgG induced ceramide accumulation and podocyte senescence. Obesity also heightened glomerular macrophage infiltration, and macrophage depletion or macrophage-specific FcRn knockout significantly reduced glomerular IgG deposition and protected against podocyte injury and senescence. Conclusions: FcRn-expressing macrophages increased obesity-induced IgG retention in glomeruli, which led to podocyte ceramide overload and senescence.

BACKGROUND:Lung cancer remains the leading cause of cancer-related mortality globally, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Despite extensive research efforts, the role of transcription factors in LUAD progression remains largely uncharacterized. In this study, we focused on ZNF266, a transcription factor whose impacts on LUAD have not been investigated. METHODS:Using high-throughput sequencing data, we observed a significant downregulation of ZNF266 expression in LUAD tissues. To validate this finding, we conducted a retrospective analysis of nearly three thousand LUAD patients' data from public databases and our institution. Functional studies were performed using cell lines, organoids, and xenograft models to assess the role of ZNF266 in LUAD progression. RNA sequencing, chromatin immunoprecipitation, DNA pull-down assays, and dual-luciferase reporter assays were employed to elucidate the underlying mechanism. Additionally, adeno-associated virus (AAV)-mediated overexpression of ZNF266 was used to evaluate its therapeutic potential. RESULTS:Patients with low ZNF266 expression had poorer prognosis compared to those with high expression. ZNF266 inhibits the malignant phenotypes of LUAD, including proliferation, migration, and invasion. Mechanistically, ZNF266 binds to the promoter region of CA9, suppressing its transcription. This leads to a reduction in intracellular pH and subsequent inhibition of the mTOR signaling pathway, which is crucial for cancer cell growth and survival. Furthermore, AAV-mediated overexpression of ZNF266 significantly inhibited tumor growth in patient-derived xenograft models. CONCLUSIONS:Our study demonstrated that ZNF266 inhibits LUAD progression in a pH-dependent manner via modulating CA9 expression, uncovering its therapeutic significance for LUAD treatment.

ObjectiveTo investigate the protective effect and mechanism of berberine on renal tubular epithelial cell injury in diabetic kidney disease.MethodsMale 8-week-old db/db and db/m mice were randomly divided into two groups， and respectively treated with oral gavage of berberine 300 mg/kg/day for 8 weeks （berberine treatment group）， and the same volume of normal saline （control group）. Changes in body weight， blood glucose and urea nitrogen were detected. Renal pathology was observed. Fenal tubular mitochondrial function and fatty acid oxidation level were detected. Protein level of carnitine palmitoyltransferase-1 alpha （CPT1α） in renal tubule was detected. Human renal cortical proximal tubular epithelial cells were cultured in vitro and divided into control group， berberine group， high-glucose group， and high-glucose＋berberine group. Protein levels of CPT1α and oxidative stress in cells were examined.ResultsBerberine did not significantly change the body weight， blood sugar and urea nitrogen levels of db/m mice， but significantly decreased them in db/db mice. The hematoxylin and eosin （H&E） and periodic acid-Schiff （PAS） staining showed that berberine significantly alleviated pathological damage of renal tubule in db/db mice， and accelerated CPT1α-mediated fatty acid oxidation in renal tubule. In vitro experiments showed that berberine significantly reduced high-glucose-induced oxidative stress， and reversed the inhibited CPT1α and fatty acid oxidation induced by high-glucose environment.ConclusionBerberine attenuates pathological damage and improves renal function in diabetic kidney disease by upregulating CPT1α-mediated fatty acid oxidation in renal tubules.

Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms. An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine’s effects on ferroptosis. Metabolic fate was studied using 15N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues. Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models. Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.

Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.

BACKGROUND:Ferroptosis, a form of cell death reliant on iron metabolism dysregulation and lipid peroxidation, has emerged as a promising target for improving tumor drug resistance. This study aims to unveil the underlying molecular mechanisms of Kruppel-like factor 13 (KLF13) in ferroptosis and chemotherapy sensitivity in lung adenocarcinoma (LUAD). RESULTS:We conducted RNA sequencing on lung adenocarcinoma cells treated with ferroptosis inducers and found that the expression level of KLF13 changed during ferroptosis, suggesting its potential involvement in this process. Subsequently, we generated stable cell lines overexpressing and knocking down KLF13. Cytotoxicity assays and reactive oxygen species (ROS) detection demonstrated that overexpression of KLF13 promoted ferroptosis induced by IKE and RSL3 in LUAD cells, whereas silencing KLF13 inhibited ferroptosis. Furthermore, overexpression of KLF13 enhanced the chemotherapeutic efficacy of cisplatin and pemetrexed. RNA-seq, qPCR, and western blot experiments revealed that KLF13 downregulated the RNA and protein expression of GPX4. ChIP assays and dual-luciferase reporter gene assays indicated that KLF13 directly bound to the promoter region of GPX4, inhibiting transcriptional activity of GPX4. Additionally, overexpression and knockdown of GPX4 could reverse the effects of KLF13 on ferroptosis and chemosensitivity. These findings were further confirmed through immunohistochemical staining and animal experiments. CONCLUSIONS:Our study reveals that KLF13 promotes ferroptosis in LUAD by inhibiting GPX4, thereby enhancing sensitivity to chemotherapy drugs. Overall, targeting KLF13 may contribute to developing new therapeutic strategies for LUAD.

Background Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear. Methods The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation. Results USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation. Conclusion This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.

BACKGROUND: Lung adenocarcinoma (LUAD) remains a significant contributor to cancer incidence and mortality, with transcription factors playing pivotal roles in its progression and serving as potential therapeutic targets. RESULTS: Through an extensive analysis of expression data from over a thousand LUAD samples, we identified zinc finger protein 146 (ZNF146) as a transcription factor significantly overexpressed in LUAD, closely associated with poor patient outcomes. Functional studies using knockout and re-expression experiments in LUAD cell lines confirmed that ZNF146 robustly promotes cell proliferation. RNA-seq and ChIP-seq data integration further revealed two key downstream effectors of ZNF146: murine double minute 2 homolog (MDM2) and phosphoglycerate dehydrogenase (PHGDH). Our results demonstrated that ZNF146 accelerates LUAD progression via the MDM2/p53 pathway and PHGDH-mediated regulation of ferroptosis. CONCLUSIONS: Our findings indicate that targeting ZNF146 could be an effective strategy in treating LUAD, supported by evidence from adeno-associated virus-mediated inhibition of ZNF146, which suppressed tumor growth in patient-derived organoids and xenograft models.

Renal fibrosis is a hallmark of diabetic kidney disease (DKD), and currently available therapies offer limited efficacy. Artesunate (ART), a repurposed antimalarial agent, has recently demonstrated potential in mitigating renal fibrosis. This study aimed to investigate whether ART protects mitochondrial integrity and attenuates fibrosis in tubular epithelial cells (TECs) via the dual-specificity phosphatase 1 (DUSP1) pathway. Mitochondrial morphology and DUSP1 expression were examined in kidney tissues from DKD patients and db/db mice. ART (25 mg/kg) was administered to db/db mice to evaluate its in vivo effects on fibrosis, mitochondrial dynamics, and inflammation. In vitro, TECs stimulated with high glucose were used to assess mitochondrial function and fibrotic response after ART treatment. Mechanistic studies included RNA sequencing, molecular docking, and genetic modulation (DUSP1 knockdown and overexpression). Mitochondrial swelling, cristae disruption, and TFAM downregulation were observed in both human DKD samples and db/db mice, correlating with tubulointerstitial fibrosis. ART treatment restored mitochondrial structure, reduced fibrotic markers, and suppressed inflammatory cytokines in vivo. In vitro, ART reversed high-glucose-induced mitochondrial dysfunction and fibrotic signaling. Mechanistically, ART directly bound to and stabilized DUSP1, thereby inhibiting MAPK signaling. Knockdown of DUSP1 abolished the protective effects of ART, while DUSP1 overexpression mimicked ART's therapeutic actions. Notably, DUSP1 expression was significantly reduced in DKD patients, associated with greater fibrosis and worse renal function. ART attenuates renal fibrosis and restores mitochondrial homeostasis in DKD through DUSP1 stabilization and MAPK pathway inhibition. These findings support ART as a potential therapeutic agent targeting mitochondrial integrity and inflammation in diabetic kidney disease.

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with the tumor microenvironment (TME) playing a critical role in its progression. Metabolic reprogramming, particularly lactate accumulation, drives immune suppression within the TME. Utilizing single-cell RNA sequencing (scRNA-seq) of 30 LUAD samples, genome-wide association studies (GWAS) involving 29,863 patients and 55,586 controls, and clinical data from 220 LUAD patients, we identified N-Myc downstream-regulated gene 1 (NDRG1) as a key pathogenic gene in LUAD, strongly associated with tumor progression and poor prognosis. Mechanistic studies revealed that NDRG1 stabilizes lactate dehydrogenase A (LDHA) by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation. This process fosters immune suppression by inducing M2 macrophage polarization, impairing CD8+ T cell function, and upregulating immunosuppressive genes. Furthermore, histone H3K18 lactylation in macrophages exacerbates this immunosuppressive state. Clinically, elevated NDRG1 expression correlates with increased PD-L1 levels, a higher abundance of immunosuppressive macrophages, and reduced CD8+ T cell infiltration, contributing to immunotherapy resistance. Conversely, low NDRG1 expression is associated with enhanced CD8+ T cell infiltration and improved therapeutic outcomes. Preclinical studies demonstrated targeting NDRG1 suppresses tumor growth, alleviates immune suppression, and boosts anti-PD-L1 efficacy. These findings establish NDRG1 as a critical LUAD regulator and a promising immunotherapy target.

Idiopathic membranous nephropathy (IMN) is a glomerular disease that is prevalent in elderly males. The pathogenesis of IMN includes abnormal autoimmunity and complement activation, both of which leading to the damage of the glomerular filtration structure. Meanwhile, due to the pathological changes in the kidney, certain coagulation-related proteins are leaked from urine, resulting in the imbalance of coagulation homeostasis. Recent studies have indicated the interaction between complement and coagulation systems, while the aberration of both is common in IMN. In this review, we summarize the subsistent and underlying pathogenesis that ensue from complement-coagulation crosstalk and present the emerging evidence in this evolving field.

Chronic kidney disease (CKD) is a worldwide public health problem. Podocyte damage is a hallmark of glomerular diseases including focal segmental glomerulosclerosis (FSGS) and one of the leading causes of CKD. Lysine methylation is a crucial post-translational modification. Beyond epidemic regulation, various lysine methyltransferases have been recently reported to participate in disease progression, including cancers and kidney diseases. Among them, Methyltransferase-like 10 (METTL10), is recognized as a gene associated with estimated glomerular filtration rate (eGFR) and CKD risk. However, its role in podocyte damage remains unclear. We identified the differentially expressed genes(DEGs)in podocyte injury by bioinformatics analysis. Patients diagnosed as idiopathic FSGS by renal biopsy were enrolled. Mouse model was established by Adriamycin(ADR) and urinary albumin/ creatinine ratio(UACR) was detected. Murine podocyte cell line was stimulated with ADR. We determined METTL10 was one of the significantly downregulated genes in damaged podocytes, confirmed the decreased glomerular expression of METTL10 in patients with idiopathic FSGS and in mice with ADR-induced nephrosis, respectively. Moreover, we found a negative correlation between glomerular METTL10 levels and UACR in mice. METTL10 was reduced in ADR-treated podocytes, accompanied by podocyte dedifferentiation (loss of synaptopodin, podocin, nephrin, WT-1) and acquisition of mesenchymal cell markers (snail, desmin, pax2). Knockdown of METTL10 promoted their dedifferentiation. METTL10 regulates podocyte dedifferentiation under damaging stimuli and protects podocytes.

Secretory phospholipase A2 group IB (sPLA2-IB) and M-type phospholipase A2 receptor (PLA2R) are closely related to proteinuria and idiopathic membranous nephropathy (IMN). Podocytes are important components of the glomerular filtration barrier and glucose metabolism, including glycolysis and tricarboxylic acid (TCA) cycle, is crucial for maintaining podocyte physiological function. Aberrant energy metabolism has been reported in proteinuria diseases, including diabetic nephropathy. However, altering energy states in podocytes in IMN remain unknown. The study aimed to determine whether sPLA2-IB induces energy metabolism abnormalities in podocytes. Cultured podocytes were treated with sPLA2-IB. siRNAs were used to knockdown expression of HIF-1α and PLA2R. Adenosine triphosphate (ATP) levels, the oxygen consumption rate and lactate content were assessed. Key enzyme of glycolysis, PKM2 and LDHA, TCA cycle-related enzymes and mTOR/HIF-1α pathway, were analyzed by PCR and immunoblotting. MTT assay was used for cell viability and phalloidin for cytoskeleton staining. sPLA2-IB induced insufficient energy states in podocytes, by decreased ATP production, increased lactate accumulation and reduced oxygen consumption rates. Under sPLA2-IB stimulation, LDHA and PKM2 were increased, while TCA cycle-related enzymes (CS, FH and SDHD) were decreased, with upregulated mTOR and HIF-1α. Mechanically, HIF-1α knockdown mitigated sPLA2-IB -induced LDHA upregulation and downregulated TCA cycle-related enzymes. Rapamycin (inhibitor of mTOR) reversed decreased ATP levels and oxygen consumption. 3-MA (activator of mTOR) aggravated lactate production. PLA2R knockdown reversed PKM2 and LDHA upregulation, FH and SDHD downregulation, and increased mTOR and HIF-1α expression. PLA2R activation by sPLA2-IB caused abnormal energy states in podocytes. The underlying mechanism involved the activation of mTOR/HIF-1α pathway.

AIMS:In diabetic kidney disease (DKD), Angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) are key treatments but may cause hyperkalemia. This randomized controlled trial (RCT) firstly evaluates sodium zirconium cyclosilicate (SZC) to optimize renin-angiotensin-aldosterone system inhibitor (RAASi) use in DKD, addressing evidence gaps in this field. METHODS:This 24-weeks prospective multicenter study enrolled 86 DKD patients at hyperkalemia risk to SZC + ACEIs/ARBs or ACEIs/ARBs alone. PRIMARY OUTCOME:ACEIs/ARBs dose up-titration at week 12. Exploratory outcomes included urinary albumin-to-creatinine ratio (UACR), serum creatinine, and blood pressure (BP). RESULTS:At week 12, 55.81 % of patients in the SZC + ACEIs/ARBs arm up-titrated their ACEIs/ARBs dosage (95 % confidence interval [CI]: 39.88 %-70.92 %), compared to 27.91 % in the ACEIs/ARBs arm (95 % CI: 15.33 %-43.67 %, P = 0.009). UACR decreased by 63.46 mg/g in the SZC + ACEIs/ARBs arm at week 24, while increasing by 316.87 mg/g in the ACEIs/ARBs arm (least squares mean difference [LSMD]: -333.63 mg/g [95 % CI: -1148.73 to 481.47]; Per-Protocol Set). BP reductions were greater numerically in the SZC + ACEIs/ARBs arm (systolic: -1.7 mmHg; diastolic: -1.4 mmHg). CONCLUSIONS:SZC reduced hyperkalemia-related RAASi discontinuation risk, improved proteinuria and BP, supporting its prophylactic use in DKD patients on RAASi.

Retinol, a pivotal regulator of cellular growth and apoptosis, has garnered substantial attention for its intricate involvement in cancer development. To explore Vitamin A's impact on lung adenocarcinoma (LUAD), we utilized comprehensive datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to dissect the intricate role of retinol in cancer progression. The unsupervised clustering analysis, grounded on retinol metabolism gene sets, divided patients into two distinct clusters, with cluster 1 exhibiting significantly inferior survival outcomes. Through differential analysis, we uncovered 349 differentially mutated and 394 differentially expressed genes between these clusters. Leveraging these discoveries, we built a seven-gene signature model that precisely predicted poorer survival for patients with a higher risk score, which was subsequently validated in four independent GEO cohorts, demonstrating its robustness and reliability. Our drug sensitivity analysis further revealed that high-risk patients were more susceptible to gefitinib and erlotinib. Notably, leveraging gene dependency scores and RNA-seq data from LUAD cell lines, we identified Phosphoribosylaminoimidazole Carboxylase And Phosphoribosylaminoimidazolesuccinocarboxamide Synthase (PAICS) as a potential therapeutic target. Single-RNA sequencing confirmed PAICS's predominant expression in cancer cells, and functional assays underscored its oncogenic role in promoting cell proliferation, migration, and invasion. These novel findings offer profound insights into potential therapeutic avenues for LUAD patients with poor prognoses, paving the way for future research endeavors.

Chronic kidney disease （CKD） patients are at an elevated risk of thromboembolism, cerebral infarction and myocardial infarction. The incidence of fatal thrombotic complications has been rising over the years. It may be attributed to uremic toxin accumulation, blood coagulation dysfunction, platelet activation and abnormal hemostasis associated with CKD. Therefore dose adjustments and drug selections for antiplatelet and anticoagulant therapy should be based upon the level of glomerular filtration rate （GFR）. This review summarized the underlying mechanisms of thromboembolic complications and recent advances of anticoagulant therapy for non-dialysis CKD patients.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, with high incidence and poor prognosis. Revealing mechanisms of ESCC progression and developing new therapeutic targets remains crucial. The aim of this study was to elucidate the molecular mechanism of miR-30c-5p in regulating the malignant progression of ESCC. Methods: TCGA, GEO, and other datasets were used to analyze the differential expression of miR-30c-5p in ESCC and adjacent tissues, and its impact on prognosis. Then the effects of miR-30c-5p on the proliferation, migration, and invasion of TE-1 and Eca9706 cells were investigated through proliferation experiments, transwell and wounding healing assays. The regulatory mechanism of miR-30c-5p on the PI3K/ AKT signaling pathway and its interaction in cancer progression were investigated through Western blots, dual-luciferase reporter assay, and rescue experiments. Results: miR-30c-5p was significantly downregulated in ESCC tissue and represented a poor prognosis. miR-30c-5p mimic significantly inhibited the proliferation, migration, and invasion ability of ESCC, while miR-30c-5p inhibitor significantly promoted tumor cell progression. Through bioinformatic analysis and experimental results, miR-30c-5p interacted directly with PIK3CA mRNA and inhibited subsequent signaling pathway activation. PIK3CA activator could eliminate the inhibitory effects of miR-30c-5p mimic on the progression of ESCC, while PIK3CA inhibitors could rescue the promoting effect of miR-30c-5p inhibitor group cells. Conclusions: In summary, we found that miR-30c-5p inhibited the proliferation, invasion and migration of ESCC by inhibiting PI3K/AKT signaling pathway for the first time, and this study is expected to provide a novel insight and potential therapeutic target for managing ESCC.

The tumor microenvironment (TME) is intricately associated with cancer progression, characterized by dynamic interactions among various cellular and molecular components that significantly impact the carcinogenic process. Notably, neutrophils play a crucial dual role in regulating this complex environment. These cells oscillate between promoting and inhibiting tumor activity, responding to a multitude of cytokines, chemokines, and tumor-derived factors. This response modulates immune reactions and affects the proliferation, metastasis, and angiogenesis of cancer cells. A significant aspect of their influence is their interaction with the endoplasmic reticulum (ER) stress responses in cancer cells, markedly altering tumor immunodynamics by modulating the phenotypic plasticity and functionality of neutrophils. Furthermore, neutrophil extracellular traps (NETs) exert a pivotal influence in the progression of malignancies by enhancing inflammation, metastasis, immune suppression, and thrombosis, thereby exacerbating the disease. In the realm of immunotherapy, checkpoint inhibitors targeting PD-L1/PD-1 and CTLA-4 among others have underscored the significant role of neutrophils in enhancing therapeutic responses. Recent research has highlighted the potential of using neutrophils for targeted drug delivery through nanoparticle systems, which precisely control drug release and significantly enhance antitumor efficacy. This review thoroughly examines the diverse functions of neutrophils in cancer treatment, emphasizing their potential in regulating immune therapy responses and as drug delivery carriers, offering innovative perspectives and profound implications for the development of targeted diagnostic and therapeutic strategies in oncology.