Calcium oxalate (CaOx) nephrolithiasis is a globally prevalent disease with complex pathogenesis and limited targeted therapies. The imbalance between renal tubular epithelial cell (RTEC) injury and repair serves as a key driver of stone formation. Under hyperoxaluric or crystal-induced stress, RTECs undergo multiple regulated cell death pathways including apoptosis, pyroptosis, ferroptosis, and necroptosis, alongside autophagic dysfunction. These processes trigger the release of damage-associated molecular patterns and inflammatory mediators that amplify local inflammation and enhance crystal adhesion. Importantly, tubular repair after injury is not a uniform process but diverges into three distinct outcomes, including adaptive tubular regeneration, repair failure, and fibrogenic maladaptive repair. Persistent RTEC injury-repair imbalance disrupts tubular barrier integrity, perpetuates self-sustaining inflammatory cascades, and upregulates epithelial crystal adhesion molecules, collectively remodeling the renal microenvironment into a stable pro-stone niche that facilitates CaOx crystal deposition and stone formation. This review systematically summarizes the types of RTEC injury, the compromised repair pathways and their regulatory networks. It also discusses emerging therapeutic strategies aimed at correcting the injury-repair imbalance axis to provide new directions for the prevention and treatment of CaOx nephrolithiasis.

The contribution of macrophage polarization dysregulation to calcium oxalate (CaOx) nephrolithiasis remains poorly defined. Here, we identify the long non-coding RNA growth arrest-specific transcript 5 (GAS5) as a critical driver of pro-inflammatory M1 macrophage polarization through the Notch/NF-κB/NLRP3 axis, thereby aggravating CaOx-induced renal injury. In human macrophages, calcium oxalate monohydrate (COM) stimulation upregulates GAS5 expression, which functions as a competing endogenous RNA by sequestering miR-449c-5p, leading to derepression of Notch1 and amplification of downstream inflammatory signaling. Activated Notch1 engages TLR4 to trigger NF-κB/NLRP3 inflammasome activation, promoting M1 polarization, inflammatory cytokine release, tubular epithelial pyroptosis, and enhanced crystal adhesion. Given the limited conservation of lncRNA-miRNA interactions across species, we further delineated a species adaptive regulatory mechanism in mice. In murine macrophages, GAS5 enhances Notch1 signaling through sequestration of a distinct miRNA, miR-325-3p, thereby preserving the core ceRNA logic while employing different miRNA mediators. In vivo, macrophage enriched GAS5 overexpression exacerbates Gly induced CaOx deposition, renal dysfunction, and inflammation, whereas pharmacological inhibition of Notch signaling or TLR4 knockdown markedly attenuates these effects. Conversely, restoration of the corresponding regulatory miRNAs suppresses Notch1 signaling and favors anti-inflammatory macrophage polarization. Together, these findings uncover a conserved, yet species-adaptive, GAS5 centered ceRNA regulatory framework that governs macrophage driven inflammation and renal injury in CaOx nephrolithiasis, highlighting GAS5-Notch signaling as a potential immunomodulatory target for nephrolithiasis.

The pathogenesis of renal calcium oxalate (CaOx) stone is multifaceted and closely associated with metabolic disturbances. Palmitic acid (PA), a major saturated fatty acid, has emerged as a key contributor to CaOx stone formation. In this study, high-throughput drug screening identified probucol as a potential therapeutic agent capable of alleviating PA-mediated renal CaOx crystal formation in vitro and in vivo. Mechanistically, PA upregulates krüppel-like factor 5 (KLF5), which transcriptionally activates peroxisome proliferator activated receptor gamma (PPARγ) and thereby drives lipotoxicity. Probucol directly binds to arginine-440 (Arg440) within the zinc finger DNA-binding domain of KLF5, competitively inhibiting its DNA-binding ability. This inhibition suppresses PPARγ expression and mitigates PPARγ-mediated lipotoxicity. Collectively, our findings identify KLF5 as a novel intracellular target of probucol, and highlight its therapeutic potential in treating PA-mediated renal CaOx stone formation by mitigating lipotoxicity.

Arsenic (As) and cadmium (Cd) frequently co-occur in groundwater and preferentially target renal proximal tubules. Although each metal can independently induce ferroptosis-related processes, the integrated molecular responses to co-exposure remain incompletely understood. In this study, human HK-2 cells were exposed for 24 h to As (10 µM), Cd (10 µM), or their combination (5 µM + 5 µM). We evaluated ferroptosis- and oxidative stress-related gene expression, key protein markers, and lipid peroxidation. Combined exposure produced the most consistent transcriptional alterations across pathways involved in iron homeostasis, glutathione metabolism, lipid remodeling, mitochondrial function, autophagy, and NRF2 signaling. At the protein level, GPX4 and SLC7A11 were decreased, whereas ACSL4, PTGS2, and TFR1 were increased, accompanied by reduced ferritin and elevated LC3-II. Lipid peroxidation analysis further demonstrated a marked increase in oxidized lipid fractions in the co-exposure group. These findings indicate that arsenic and cadmium act synergistically to impair antioxidant defenses, enhance iron availability, and promote lipid peroxidation, thereby driving ferroptosis in renal epithelial cells. Targeting ferroptosis and iron metabolism may represent a promising strategy for mitigating mixed-metal-induced nephrotoxicity.

Background Acute kidney injury (AKI) remains a major clinical challenge and is largely driven by excessive oxidative stress, inflammatory responses, and tubular cell apoptosis. However, effective therapeutic strategies that simultaneously target these pathological processes are still lacking.Results We developed a pH-responsive ultrasmall Fe-kaempferol (Fe-Kae) nanoplatform with coordinated antioxidant and anti-inflammatory activities for AKI treatment. Owing to their ultrasmall size and pH-responsive properties, Fe-Kae nanoparticles preferentially accumulated in injured renal tissues and exhibited robust renoprotective effects in multiple murine AKI models, including ischemia-reperfusion injury, cisplatin-induced nephrotoxicity, and calcium oxalate-induced kidney injury. Integrated transcriptomic and metabolomic analyses of ischemia-reperfusion-injured kidneys revealed that Fe-Kae treatment markedly enhanced efferocytosis-associated pathways and induced coordinated metabolic reprogramming, characterized by optimized tricarboxylic acid cycle activity and enhanced glutathione metabolism.Conclusions This study establishes a nanomedicine-based therapeutic strategy that couples efferocytosis enhancement with metabolic reprogramming to achieve effective renoprotection. Our findings highlight pH-responsive ultrasmall metal-polyphenol nanoplatforms as a promising paradigm for the treatment of AKI.

Exposure to fine particulate matter (PM2.5) is associated with renal injury and chronic kidney disease (CKD) progression, yet its mechanisms remain incompletely understood. In this study, we exposed mice to urban PM2.5 at an environmentally relevant dose via the respiratory tract and combined this with renal ischemia-reperfusion injury (IRI) to systematically assess its effects on kidney function and structure. Meanwhile, we investigated the relevant molecular biological mechanisms underlying renal functional and structural damage mediated by the lung-kidney axis following repeated intratracheal PM2.5 exposure. The results indicated that PM2.5 exposure significantly exacerbated renal dysfunction, tubular injury, and fibrosis, accompanied by increased lipid droplet accumulation and upregulation of fibrotic markers, and adenylate cyclase 3 (ADCY3) was identified as a critical target in this pathological process. Mechanistically, PM2.5 induced systemic inflammation and elevated circulating interleukin-6 (IL-6) levels, with alveolar macrophages likely contributing as a key source. Elevated IL-6 subsequently suppressed the function of ADCY3-CREB-PGC1α signaling pathway, leading to impaired fatty acid β-oxidation (FAO), enhanced glycolysis, mitochondrial dysfunction, oxidative stress, and fibrotic progression. Functional experiments further confirmed that blocking IL-6 signaling or overexpressing ADCY3 mitigated renal tubular epithelial cell injury, lipid metabolic dysregulation, and fibrotic responses mediated by PM2.5 exposure both in vivo and in vitro. In conclusion, this study offers a new insight into the intricate molecular mechanisms through which PM2.5 exposure exacerbates renal injury and CKD progression, suggesting that the IL-6/ADCY3 signaling pathway plays a crucial role in renal injury induced by PM2.5 exposure.

Acute kidney injury (AKI) represents a critical clinical condition marked by abrupt deterioration of renal function, primarily driven by oxidative stress, inflammation, and apoptosis. However, effective targeted therapies remain limited. Here, a smart, biomimetic nanoplatform (CeAst@MK) that synergistically addresses oxidative and inflammatory injury in AKI is reported. CeAst nanoparticles are formed via coordination between Ce 3 ⁺ ions and astragalin (Ast), a natural flavonoid with intrinsic ROS‐scavenging and anti‐inflammatory properties. To enhance immune evasion and renal targeting specificity, CeAst is cloaked with macrophage membranes (MCM) and modified with a kidney‐targeting peptide (KTP), yielding the final CeAst@MK system. The platform exhibits pH‐responsive release in the acidic microenvironment of injured renal tissues, enabling precise and rapid therapeutic delivery. In both LPS‐ and ischemia reperfusion‐induced AKI models, CeAst@MK significantly improves renal function, suppresses proinflammatory cytokines, and promotes M2 macrophage polarization. Mechanistically, it modulates PI3K/Akt and NF‐κB pathways, achieving dual antioxidative and anti‐inflammatory effects. This study presents a translationally promising nanotherapeutic system integrating natural antioxidants, biomimetic camouflage, and tissue‐specific delivery, offering an effective and precise strategy for AKI intervention.

An imbalance exists between renal tubular epithelial cells (RTECs) injury and repair in kidney stone disease, yet the underlying mechanism remains largely unclear. Here, we found that gasdermin D (GSDMD)-mediated pyroptosis occurred in both patients and mice with calcium oxalate (CaOx) nephrolithiasis, and the expression levels of NOD-like receptor protein 3 (NLRP3) and GSDMD were associated with the severity of kidney stones. Deficiency of GSDMD alleviated renal tubule damage and inflammatory response, ultimately inhibiting renal injury and crystal deposition. Additionally, we found that charged multivesicular body protein 4B (CHMP4B)-dependent cell repair was activated during pyroptosis of RTECs; however, the enhancement was insufficient to offset the damage. Importantly, Ca2+ fluxes during pyroptosis induce activation of the CHMP4B-dependent cell repair machinery. Overexpression of CHMP4B attenuates cell death and reduces the severity of kidney stones. Notably, combining the overexpression of CHMP4B with a GSDMD inhibitor demonstrates heightened efficacy in ameliorating kidney damage and crystal deposition induced by glyoxylate (Gly). Taken together, these results highlight the imbalance between GSDMD-mediated pyroptosis and CHMP4B-dependent cell repair as a driver for CaOx kidney stone formation. Our findings provide new insights and potential therapeutic targets for CaOx kidney stones.

The phospholipid-modifying enzyme MBOAT2 plays a crucial role in iron homeostasis by inhibiting iron sequestration, thus preventing iron-induced cell death. It achieves this by remodeling the phospholipid composition of cell membranes through phospholipid metabolism. Although multiple studies have highlighted the significance of MBOAT2 in tumorigenesis, a comprehensive pan-cancer analysis has not been conducted to date. In this study, we analyzed the expression levels of MBOAT2 using RNA sequencing data from the TCGA and GTEx databases. We also investigated MBOAT2 protein information using resources such as the Human Protein Atlas (HPA), GeneCards, and String databases. To assess the prognostic value of MBOAT2, we conducted survival analysis based on clinical data from TCGA. Additionally, we performed enrichment analysis using the R package “clusterProfiler” and explored the relationship between MBOAT2 expression and immune cell infiltration, as well as immune checkpoint interactions in TCGA datasets. Furthermore, we examined the correlation between MBOAT2 expression and clinical pathology through immunohistochemical analysis of breast, prostate, lung, and liver cancer tissues in the HPA database. Finally, western blotting was used to validate MBOAT2 protein expression in breast and prostate cancer cell lines. Our analysis revealed that MBOAT2 was highly expressed in a wide range of cancer types, with its expression correlating with improved survival outcomes in the TCGA dataset. Moreover, we found a significant association between MBOAT2 expression and immune regulation, particularly in relation to immune cell infiltration and immune checkpoint interactions. MBOAT2 holds promise as a prognostic biomarker and may serve as a target for immunotherapy in various malignancies. Further investigation into its role in cancer immunity could offer new insights into potential therapeutic strategies.

Background:Lower pole renal stones measuring 1-2 cm remain challenging to treat. While mini-percutaneous nephrolithotomy (mini-PCNL) provides high stone-free rates (SFRs), it carries tract-related morbidity. Flexible ureteroscopy (f-URS) is less invasive but limited in SFR. The flexible and navigable suction ureteral access sheath (FANS) has shown promise in improving stone evacuation and intrarenal pressure control. We hypothesize that FANS f-URS is non-inferior to mini-PCNL for patients with 1-2 cm lower pole stones in SFR. Study Design:The FLAME trial is an international, multicentre, randomized, non-inferiority study directly comparing FANS-f-URS with mini-PCNL in this setting. Endpoints:The primary outcome is immediate SFR within 72 hours on low-dose CT. Secondary outcomes include SFR at 1 month, operative time, postoperative pain, hospital stay, complications (Clavien-Dindo) and quality-of-life changes. Patients and Methods:A total of 640 adults with CT-confirmed 1-2 cm lower pole renal stones will be randomized 1:1 to undergo FANS-f-URS or mini-PCNL across 20 high-volume urology centres worldwide. Randomization is centralized and stratified by site. Radiologists and statisticians will remain blinded to allocation. Sample size was calculated assuming an 85% SFR for both arms, an 8.5% non-inferiority margin, 80% power and 15% attrition. Analyses will follow both intention-to-treat and per-protocol principles. Trial registration:ClinicalTrials.gov NCT07159035.

With the rapid expansion of industrial and commercial applications, graphene-based 2D nanomaterials such as graphene oxide (GO) are increasingly released into the environment, raising concerns about their environmental accumulation and the likelihood of human exposure. While previous studies have primarily focused on the cytotoxic effects of pristine GO (P-GO) at high exposure doses, the biological effects of GO under real environmental conditions remain poorly understood. Notably, atmospheric environmental media, such as ozone, can significantly alter the physicochemical properties of GO, thereby modulating its biological effects. In this study, we employed a non-direct toxicity dose to demonstrate that ozone aging can significantly modify the physicochemical properties of GO and enhance its low-dose exposure-mediated pro-tumor progression effect. Mechanistically, ozone-aged GO (O-GO) treatment increases the membrane localization of integrin αV, leading to the activation of the PI3K/AKT/mTOR signaling pathway, which drives bladder tumor proliferation. Furthermore, O-GO enhances the TGF-β signaling pathway by upregulating the expression levels of the TGF-β receptor, promoting bladder tumor cell invasiveness and metastasis. These findings provide novel insights into the tumor-promoting effects of GO at non-direct toxicity dose and emphasize the necessity of considering environmental aging process when assessing its environmental health and safety (EHS) risks. Given the expanding use of graphene-based materials in daily human life, our study highlights the urgent need for greener development strategies to mitigate potential health risks associated with GO exposure.

To assess the efficacy and safety of flexible ureteroscopic lithotripsy (f-URL) assisted by the tip-bendable suction ureteral access sheath (SUAS) and mini-percutaneous nephrolithotomy (mPCNL) for the treatment of simple lower calyx renal calculi. A prospective randomized controlled trial was conducted on 102 patients with simple lower calyx renal calculi (with a diameter of 1 3 cm) admitted to the Second Hospital of Tianjin Medical University from December 2023 to February 2025. The patients were randomly assigned to the SUAS f-URL group (n = 49) and the mPCNL group (n = 53). The primary endpoint of the study was the immediate stone-free rate (SFR), while the secondary endpoints included operative time, anesthesia time, visual analogue scale (VAS) pain score, estimated blood loss, complication rate, length of hospital stay, hospitalization cost, and the SFR at 30 days postoperatively. The two groups had comparable baseline characteristics. The SUAS f-URL group demonstrated a similar immediate SFR compared to the mPCNL group (67.35

Micro-nanoplastics (MNPs) are ubiquitously present in various natural habitats, and the kidney plays a critical role in eliminating metabolic waste from the body. Therefore, nephrotoxicity studies of MNPs are necessary. Consequently, we conducted a study utilizing a mouse model that underwent autonomous inhalation of polystyrene nanoplastics (PS-NPs) to investigate the impact of airborne nanoplastics (NPs) on kidney. The results demonstrated that airborne NPs could accumulate within the kidney subsequent to pulmonary entry. Transcriptome analysis showed that exposure to airborne NPs persistently interfered with important signaling pathways including oxidative stress, inflammation, and coagulation, which activated the NR4A1/CASP3 and TF/F12 signaling pathways. In vitro studies have shown that NPs were internalized by human kidney proximal tubular epithelial (HK-2) cells, leading to a range of pathological responses, and ultimately affecting cell fate. Furthermore, we pioneered the exposure of NPs to human kidney organoids. Our findings revealed a heightened sensitivity in kidney organoids towards NPs as compared to immortalized cell lines. This suggested that exposure to NPs could potentially inflict a more substantial toxic effect on the development of embryonic kidneys. In conclusion, this study has revealed the deleterious effects of exposure to airborne NPs on the mouse kidney.

Recent studies have identified a biological process called adherent-to-suspension transition (AST) as a key factor in promoting metastasis. The involvement of AST in the progression of clear cell renal cell carcinoma (ccRCC) remains largely unexplored. We comprehensively investigated the overall landscape of all 20 AST factors at the pan-cancer level. The risk stratification method and the prognostic model based on AST factors were established with consensus clustering analysis and LASSO regression algorithm. The potential molecular mechanism of AST was further investigated by multi-omics analysis and cell experiments. We found that AST factors play distinct roles in different cancer types. Consequently, we utilized AST factors to develop a risk stratification method and a prognostic model, which can effectively guide the treatment of ccRCC patients. We proposed that the promotion of AST is facilitated by SPIB through the SAA1-AKT pathway, enhancing the likelihood of ccRCC metastasis, and conducted rigorous analyses using multi-omics data and cellular experiments. Our study presents a novel risk stratification method and prognostic model for ccRCC. And we identified the SPIB-SAA1-AKT pathway as one of the potential mechanisms by which AST factors promote ccRCC metastasis.

The incidence of calcium oxalate (CaOx) urolithiasis between men and women is considerably different. However, the full-scale metabolic changes between genders with CaOx urolithiasis have not been reported. The metabolic profiles in 112 urine samples obtained from 61 males and 51 females diagnosed with CaOx stones were characterized using electrospray ionization-mass spectrometry (ESI-MS). Univariate, multivariate, and bioinformatic analyses were employed to reveal the differential metabolites and perturbed metabolic pathways between genders. In total, 30 dysregulated metabolites were identified as differential metabolites between males and females with CaOx urolithiasis. The primary metabolic pathways were caffeine metabolism, metabolic pathways, and biosynthesis of amino acids. Furthermore, 10 potential metabolites which were mostly contributed to separating the males and female were selected using feature weight calculation. These compounds included creatinine, 3-methylhistidine, n-acetylneuraminic acid, decanoyl-l-carnitine, cortisone, nicotine, 1-methyluric acid, androsterone sulfate, citramalic acid, and 1,7-dimethylxanthine. Finally, a subset of the differential metabolites was identified by receiver operating characteristic (ROC) curve analysis, including creatinine, 3-methylhistidine, n-acetylneuraminic acid, decanoyl-l-carnitine, and 1-methyluric acid (area under the curve = 0.924, 0.844, 0.846, 0.814, 0.814). These metabolites had higher risks in the CaOx stone formation of males than females. The study showed that there were a group of differential metabolites between the males and females with CaOx stones. A subset of these compounds was more closely and positively related to renal stone formation in males than females. Moreover, these metabolites may be the cause of the differences in the incidence of CaOx urolithiasis between genders.

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.

The aim is to compare the efficacy and safety between single percutaneous nephrolithotomy (sPNL) and antegrade flexible ureteroscopy-assisted percutaneous nephrolithotomy (aPNL) for the treatment of staghorn calculi. A prospective randomized controlled study was conducted at the Second Hospital of Tianjin Medical University. A total of 160 eligible patients were included, with 81 in the sPNL group and 79 in the aPNL group. The study first compared the overall differences between sPNL and aPNL. Then, the patients were divided into two subgroups: Group 1 (with less than 5 stone branches) and Group 2 (with 5 or more stone branches), and the differences between the two subgroups were further analyzed. The results showed that aPNL had a higher stone-free rate (SFR) and required fewer percutaneous tracts, with a shorter operation time compared to sPNL ( P < 0.05). Moreover, aPNL significantly reduced the need for staged surgery, particularly in patients with 5 or more stone branches. Moreover, there were no significant differences in the changes of hemoglobin levels and the need for blood transfusions between the sPNL and aPNL groups, and the incidence of multiple tracts was lower in the aPNL group. The two groups showed comparable rates of perioperative complications. We concluded that aPNL resulted in a higher SFR for staghorn calculi, and required fewer multiple percutaneous tracts, reduced the need for staged surgery, and had a shorter operative time than PNL alone, especially for patients with 5 or more stone branches. Furthermore, aPNL did not increase the incidence of surgical complications.