Aug 2026· Biomedicines· Vol 14, pp. 1852· 0 citations· 37 references
Medicine
TL;DR
The results underscore the pivotal role of USP11 in TEC apoptosis during CKD progression and suggest that targeting USP11 represents a potential therapeutic approach for CKD patients.
Abstract
Background/Objectives: Chronic kidney disease (CKD) has emerged as a critical global health challenge, driven by its high prevalence and poor prognosis. Ubiquitin-specific protease 11 (USP11), a deubiquitinating enzyme, participates in DNA damage repair, cell-cycle regulation, and immune modulation, and has been shown to promote epithelial–mesenchymal transition in renal tubular epithelial cells (TECs) during CKD progression. However, whether USP11 also plays a critical role in the apoptosis of TECs remains to be elucidated. Methods: In this study, we demonstrate that USP11 deubiquitinates and stabilizes p53, thereby activating the p53-mediated canonical mitochondrial pathway of apoptosis in cultured human proximal TECs (HK-2). Results: In uric acid (UA)-stimulated HK-2 cells, activated p53 subsequently increases mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c from the mitochondria into the cytosol, which, in turn, activates caspase 9 and caspase 3, and ultimately promotes TEC apoptosis. Inhibition of USP11 with siRNA transfection or mitoxantrone (MTX), a small-molecule inhibitor of USP11, downregulates p53 expression and blocks cytochrome c release into the cytosol, thereby significantly reducing TEC apoptosis. In vivo, both conditional genetic knockout and pharmacological inhibition of USP11 effectively reduce apoptosis of tubular cells and ameliorate kidney injury in a mouse CKD model of hyperuricemic nephropathy (HN). Conclusions: In summary, our results underscore the pivotal role of USP11 in TEC apoptosis during CKD progression and suggest that targeting USP11 represents a potential therapeutic approach for CKD patients.
Emerging evidence has established that renal tubular epithelial cell (TEC) senescence is an essential driver of renal fibrosis, while the activation of p53/p21 pathway plays a key role in initiating TEC senescence. However, the upstream regulatory mechanisms of p53/p21 pathway activation remain unclear, hindering the development of targeted anti-fibrotic therapies for chronic kidney disease (CKD). This study aimed to reveal the upstream regulator of the p53/p21 pathway and investigate its role in renal fibrosis. Here, we report that unilateral ureteral ligation (UUO) and folic acid (FA)-induced fibrotic mouse kidneys exhibited a marked senescent phenotype and activated p53/p21 pathway, accompanied by significant upregulation of ubiquitin-specific protease 11 (USP11). These changes were further verified in angiotensin II (Ang II)-stimulated HK-2 cells. Both Usp11 knockout and pharmacological inhibition with mitoxantrone (MTX) significantly alleviated UUO-induced p53/p21 pathway activation, tubular senescence and renal fibrosis. Mechanistically, USP11 directly interacted with p53 and protected it from ubiquitin-dependent degradation, thereby promoting tubular cell senescence and fibrosis. Furthermore, we identified Krüppel-like factor 4 (KLF4) as the upstream transcription factor that directly bound to the USP11 promoter and enhanced its transcription under pathological conditions. Our findings demonstrate that the KLF4-USP11-p53 axis drives tubular senescence and renal fibrosis, representing a highly promising therapeutic target for CKD.
Xin Wang, Ming Ning, Hengmin Wang et al.· Cellular Signalling· 0 citations
Ectopic deposition of calcium oxalate in the parenchyma (nephrocalcinosis) or as stones in the collecting system (nephrolithiasis) causes inflammation and oxidative stress in renal tissue. Receptor interacting serine/threonine kinase 2 (RIPK2) is a well-known mediator of oxidative stress and inflammation. However, its role in nephrocalcinosis or nephrolithiasis remains unexplored. Normal rat kidney-52E (NRK-52E) and primary renal cells were treated with calcium oxalate-monohydrate (COM) to induce nephrocalcinosis like pathological changes. siRNAs and commercially available inhibitor was used to block RIPK2's activity. Oxidative stress, inflammation, apoptosis, crystal adhesion, and changes in cell morphology were measured as endpoint markers. Exposure to COM but not to adenine, H2O2, and high-glucose significantly upregulated RIPK2 levels and induced oxidative stress, intracellular-calcium overload, and mitochondrial dysfunction. This was accompanied by nuclear factor-kappa B (NF-κB) pathway activation, increased levels of pro-inflammatory cytokines, decreased levels of anti-inflammatory cytokines, and enhanced apoptosis and epithelial-mesenchymal transition (EMT). RIPK2 silencing or pharmacological inhibition effectively mitigated these pathological changes and restored levels of antioxidant enzymes. Mechanistically, RIPK2 inhibition disrupted the NF-κB/TGF-β1 signaling and reduced CaOx crystal adhesion. Preliminary data from our previously conducted in vivo CaOx mouse model study confirmed the CaOx-induced RIPK2 upregulation. Our data strongly supports the involvement of RIPK2 in CaOx-induced renal cell damage.
G. Lahane, Arti Dhar, Audesh Bhat· Biochemical Pharmacology· 0 citations
INTRODUCTION
Contrast-induced acute kidney injury (CIAKI) is a leading cause of hospital-acquired kidney dysfunction, yet its immune-mediated pathogenic mechanisms remain poorly defined. Neutrophil extracellular traps (NETs) have been implicated in acute kidney injury. However, whether contrast agents directly induce NETs formation and whether NETs drive tubular ferroptosis through IL-33 has not been investigated.
METHODS
A prospective cohort of 330 patients undergoing coronary angiography was enrolled, with serial measurement of circulating NETs markers (myeloperoxidase, neutrophil elastase) and IL-33 at pre-contrast, two- and 12-hour time points. A murine CIAKI model was established in wild-type, peptidyl arginine deaminase 4 (PAD4) -knockout, and IL-33-knockout mice, and single-cell transcriptomic profiling of CIAKI kidneys was performed. In vitro, the serine/threonine kinase IKKα- and β-catenin-overexpressing and knockdown HK-2 cells were stimulated with iodixanol-induced NETs to evaluate how NETs regulate ferroptosis through IL-33-mediated modulation of IKKα and β-catenin.
RESULTS
CIAKI occurred in 12.1% (40/330) of patients. Circulating NETs markers and IL-33 were significantly elevated at two and 12 hours post-contrast in CIAKI compared with non-CIAKI patients. Single-cell transcriptomics identified neutrophils as the predominant source of IL-33 in CIAKI kidneys and revealed enrichment of NET formation and ferroptosis pathways. In vivo, PAD4 and IL-33 deficiency each significantly attenuated NETs and ferroptosis in CIAKI mice. Mechanistically, IL-33-enriched NETs suppressed IKKα expression, disrupted IKKα-β-catenin interaction, and impaired β-catenin nuclear translocation, thereby de-repressing long chain acyl CoA synthetase 4 transcription and amplifying ferroptotic injury. Restoration of IKKα stabilized β-catenin and attenuated NET-induced ferroptosis.
CONCLUSION
Our study demonstrates that IL-33-enriched NETs promote renal tubular ferroptosis in CIAKI by suppressing IKKα and impairing β-catenin nuclear translocation. These findings identify the NETs-IL-33-IKKα-β-catenin pathway as a novel and therapeutically actionable mechanism underlying CIAKI, providing potential targets for its diagnosis and treatment.
Mengqing Ma, Hao Zhang, Weijuan Deng et al.· Kidney International· 0 citations
Liver cancer, a prevalent and aggressive malignancy globally, is associated with high morbidity and mortality rates. Butyrate, a metabolite produced by intestinal microbiota, is capable of restricting cancer initiation and progression. However, the precise mechanisms underlying its effects on liver cancer remain poorly understood. This study utilized a CCK-8 cytotoxicity assay to demonstrate that sodium butyrate (NaB) suppresses liver cancer cell proliferation through ferroptosis and apoptosis. The involvement of ATF4/SLC7A11 signaling and mitochondrial dysfunction in NaB-induced ferroptosis and apoptosis was further investigated. Results revealed a decrease in ATF4 and SLC7A11 expression, an elevation in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and a reduction in glutathione (GSH) in NaB-treated liver cancer cells. These ferroptosis-related alterations could be reversed by an ATF4 activator. Additionally, NaB-treated liver cancer cells presented a decrease in mitochondrial membrane potential (MMP), accumulation of mitochondrial ROS, and mitochondrial damage. These cellular changes disrupted the BAX/BCL-2 balance, leading to cytochrome C release, which subsequently activated caspase9 and caspase3, initiating mitochondrial pathway apoptosis. In vivo, NaB treatment resulted in increased iron content in liver cancer tissues, along with upregulated cytochrome C, activated caspase9, and caspase3 expression; these effects were counteracted by ferrostatin-1 (Fer-1). Collectively, this study elucidates that NaB induces mitochondrial damage via ferroptosis mediated by ATF4/SLC7A11, ultimately triggering mitochondrial pathway apoptosis in hepatoma cells. These findings may offer novel insights into therapeutic strategies for hepatoma.
Xiaolan Meng, Yubin Li, Miao He et al.· PLoS ONE· 0 citations
Copper is essential for mitochondrial respiration, antioxidant defense, extracellular matrix maturation, and cellular signaling, yet disturbances in its abundance or intracellular distribution can damage the kidney through mechanistically distinct pathways. Cuproptosis is a specific copper-dependent form of regulated cell death in which copper binds lipoylated mitochondrial proteins, promotes aggregation of tricarboxylic acid cycle components, destabilizes iron–sulfur cluster proteins, and elicits FDX1- and protein lipoylation-dependent proteotoxic stress. This mechanism should be distinguished from broader copper-associated injury, including redox imbalance, glutathione depletion, respiratory-chain inhibition, senescence, apoptosis, and lysyl oxidase-mediated matrix remodeling. This narrative review examines how renal copper uptake, trafficking, and compartmentalization interact with cell-specific metabolism to shape copper-related cell fates across acute kidney injury, nephrotoxicity, renal ischemia–reperfusion injury, crystal- and lipid-related tubular injury, diabetic kidney disease, podocyte injury, chronic kidney disease and renal fibrosis, end-stage renal disease, renal cell carcinoma, and hereditary copper disorders. Mechanistic evidence is strongest in selected acute tubular, crystal-injury, and renal cancer models, in which transporter manipulation, DLAT oligomerization, iron–sulfur perturbation, or functional rescue has been demonstrated. In chronic kidney disease and fibrosis, copper-DLAT interactions, complex IV inhibition, COMMD1-SOD1 dysfunction, and ATP7A-FBLN4-LOX signaling establish pathogenic copper dependence but do not yet demonstrate a complete canonical cuproptosis pathway. By integrating disease-specific evidence with the molecular determinants of copper handling and protein lipoylation, this review identifies current therapeutic opportunities, candidate biomarkers, and key research priorities while preserving the distinction between cuproptosis and other forms of copper-associated kidney injury.
Wei Shao, Qingguo Wang, Yan-Ting Liu et al.· International Journal of Mol...· 0 citations
Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and chronic kidney disease. Oxidative stress, a key driver of renal fibrosis and a hallmark of DKD pathological changes, has been extensively studied for its role in DKD progression. However, its specific mechanisms remain unclear. Here, we show that homocysteine (Hcy) accumulation in proximal tubular epithelial cells (PTECs) is a significant contributor to mitochondrial oxidative stress in DKD. Through single-cell RNA sequencing (scRNA-seq) screening, we identify lncPTEC, a DKD-associated long non-coding RNA (lncRNA) from the PTEC cluster. Notably, we find that upregulated lncPTEC correlates with elevated albuminuria in DKD patients and exacerbates mitochondrial oxidative stress, epithelial-mesenchymal transition (EMT) and renal tubular fibrosis both in vitro and in vivo. Mechanistically, lncPTEC is transcriptionally upregulated by the transcription factor specificity protein 1 (SP1) under hyperglycemic conditions. Furthermore, lncPTEC directly interacts with the established key factor of Hcy metabolism, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), promoting its ubiquitination and degradation via the ubiquitination-related protein UBQLN1. This process leads to Hcy accumulation, mitochondrial oxidative stress, and subsequent DKD progression. Hence, our findings elucidate the role of the lncPTEC/MTHFD1 axis in Hcy-mediated mitochondrial oxidative stress, offering potential diagnostic biomarkers and therapeutic targets for DKD.
Qi-Jia Wang, Tianhui Wu, Peilin Li et al.· Cell Death and Disease· 0 citations
