Cisplatin exhibits potent antitumor efficacy but also causes dose-dependent nephrotoxicity mediated through apoptosis of renal tubular epithelial cells, which limits its clinical application. Cisplatin induces significant mitophagy in these cells; however, the mechanisms underlying its effects on apoptotic processes remain incompletely elucidated. This study investigated the mechanism by which the polyunsaturated fatty acid docosahexaenoic acid (DHA) modulates mitophagy to alleviate cisplatin nephrotoxicity. A cisplatin-induced (15 mg/kg, intraperitoneal) acute kidney injury model was established in C57BL/6J mice, with the intervention group receiving albumin-conjugated DHA (4 mg/kg). Systematic analyses revealed that cisplatin perturbed lysosomal degradation, which led to accumulation of dysfunctional mitochondria and increased apoptosis due to impaired mitophagic flux. DHA ameliorated lysosomal dysfunction, enhanced clearance of dysfunctional mitochondria, and suppressed apoptosis. Our findings suggest that blockade of mitophagic flux is a pivotal mechanism underlying cisplatin nephrotoxicity and that DHA-mediated restoration of mitophagy is a promising therapeutic strategy.

Lupus nephritis (LN) represents the most severe and frequent complication of systemic lupus erythematosus (SLE), yet its treatment remains a significant unmet clinical need. Recent advances in immunometabolism have revealed that glucose metabolic reprogramming—including shifts in glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle—plays a central role in driving pathogenic immune cell activation in SLE. However, a critical gap persists in understanding how these metabolic alterations specifically operate within the renal microenvironment to promote immune cell infiltration and intrinsic kidney cell injury in LN. This review synthesizes current evidence on the molecular mechanisms linking glucose metabolism to immune dysfunction in innate immune cells including monocytes/macrophages, neutrophils and DCs and adaptive immune cells including T cells, B cells and renal resident cells. We further discuss therapeutic strategies targeting metabolic pathways, including repurposed drugs (metformin, hydroxychloroquine, rapamycin), preclinical small molecules (PKM2, PFKFB3, LDHA, GLUT1 inhibitors), and combination therapies with biologics. Safety considerations, particularly the sensitivity of regulatory T cells (Tregs) to glycolysis inhibition, underscore the need for dose optimization. Finally, we highlight future directions, including real-time metabolic imaging, personalized glycolysis scoring, and spatiotemporal metabolic epigenetic models, which hold promise for advancing precision medicine in LN.

De novo peptide sequencing is an important pattern recognition task in computational proteomics, enabling direct identification of peptide sequences from tandem mass spectrometry (MS/MS) data for biomarker discovery, antibody characterization, and analysis of peptides absent from reference databases. State-of-the-art models encode observed spectra into latent representations for peptide prediction. However, the issue of missing fragmentation, attributable to factors such as suboptimal fragmentation efficiency and instrumental constraints, presents a formidable challenge in practical applications. To tackle this obstacle, we propose Latent Imputation before Prediction (LIPNovo), a new computational paradigm that compensates for missing fragmentation information before peptide prediction. Instead of generating raw missing data, LIPNovo performs imputation in the latent space, guided by the theoretical peak profile of the target peptide. The imputation process is formulated as a set-prediction problem, where learnable peak queries reason over observed peaks and generate latent representations of theoretical peaks through optimal bipartite matching. To move beyond static missingness patterns seen during training, we further propose LIPNovo+, a self-reflective extension that identifies fragmentation sites with unreliable latent imputation and refocuses learning on these vulnerable regions through a reflection-guided curriculum. Across four benchmark datasets, LIPNovo and LIPNovo+ consistently outperform state-of-the art methods, with gains of up to +15% in peptide precision. Code is available at https://github.com/usr922/LIPNovo.

Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is central to cellular lipid homeostasis, yet its dynamic regulation in living organisms has remained largely unobservable in real time. To overcome this barrier, we recently developed the mCherry‑eGFP‑LiveDrop (tfLiveDrop) reporter mice, in which a pH‑sensitive tandem fluorescent probe targeted to LDs via the GPAT4‑derived LiveDrop domain enables real‑time, single‑cell visualization of lipophagic flux in vivo. Using tfLiveDrop mice, we uncovered pronounced organ heterogeneity in basal lipophagy, identified an organ‑specific lipophagic inhibition in type 2 diabetes, and revealed a previously unrecognized developmentally programmed lipophagy induction that drives renal metabolic maturation. Together, these findings demonstrate that tfLiveDrop is a sensitive and versatile reporter for in vivo lipophagy research.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune connective tissue disease in which the immune system is aberrantly activated, producing various autoantibodies that target the body's tissues, particularly the kidneys. Approximately 50% of patients with lupus nephritis (LN) eventually progress to end-stage renal disease. Despite the availability of multiple therapies, their effectiveness is often limited by individual patient differences. Recent studies have identified a new signaling pathway, the cyclic GMP-AMP synthetase (cGAS)-interferon gene stimulating factor (STING) innate immune pathway. Research has indicated that the serum levels of cGAS, STING, and type I interferon are significantly higher in mice with SLE or LN compared with normal populations. Experimental findings also suggest that the absence of cGAS and STING significantly reduces autoantibody production and alleviates tissue inflammation in autoimmune mouse models. These observations highlight the potential of targeting this pathway as a treatment for patients with SLE and LN. However, significant translational hurdles remain, including contradictory evidence from murine models, a complete lack of human trial data for leading candidates, and the inherent risk of viral reactivation owing to systemic immunosuppression. This article provides an overview of the cGAS-STING pathway, discusses its relevance to SLE and LN, and summarizes over 20 inhibitors targeting cGAS/STING. Furthermore, we emphasize the key clinical challenges and prospects of targeted drugs in this pathway.

Lipophagy, a selective form of autophagy, is critical for maintaining cellular lipid homeostasis. However, understanding its dynamic regulation and pathophysiological significance in vivo has been hindered by a lack of sensitive and versatile monitoring tools. To address this gap, we generated the tfLiveDrop (mCherry-eGFP-LiveDrop) reporter mouse by integrating a tandem mCherry-eGFP fluorescent probe with the lipid droplet-targeting domain of glycerol-3-phosphate acyltransferase 4 (GPAT4, the rate-limiting enzyme in triacylglycerol synthesis), termed the LiveDrop domain. This model enables real-time, spatiotemporal visualization of lipophagic flux at single-cell resolution in living animals. We initially validated the sensitivity and specificity of the tfLiveDrop reporter in primary renal tubular epithelial cells (TECs). Systemic mapping of lipophagic activity across organs revealed pronounced heterogeneity in basal lipophagic activity under physiological conditions. Furthermore, in a model of Type 2 diabetes, we demonstrated that lipophagic flux is dysregulated in a tissue-specific manner in male mice, underscoring its pivotal role in disease-associated lipid metabolism. Notably, longitudinal tracking during kidney development uncovered a programmed wave of lipophagic activity that is essential for lipid homeostasis during renal maturation. Our findings provide a powerful and versatile platform for in vivo lipophagy research, establishing a foundation for elucidating its functional contributions to metabolic disorders and organ development.

Chronic kidney disease (CKD) is increasing globally, presenting a critical health challenge. Renal fibrosis, the main pathological feature of CKD, is poorly understood and lacks targeted therapies. Here, we reveal that 5-methylcytosine (m5C) RNA methylation, primarily mediated by methyltransferase NSUN2, is significantly upregulated in renal fibrosis. Reduction of m5C RNA methylation levels upon NSUN2 loss attenuates fibrosis responses in cells, and specific knockout of NSUN2 in renal tubular epithelial cells alleviates renal fibrosis in several disease models. Mechanistically, NSUN2 methylates and stabilizes glycine amidinetransferase (GATM) mRNA. GATM exacerbates mitochondrial fission not only by directly binding to Drp1 but also through its product creatine, collectively driving the progression of renal fibrosis. We subsequently identify an inhibitor of NSUN2 that mitigates the progression of renal fibrosis. Collectively, our study demonstrates that targeting NSUN2-mediated m5C methylation of GATM mRNA therapeutically offers a promising strategy to slow the progression of CKD.

The Cre/loxP system continues to serve as a well-established and widely adopted strategy for generating conditional gene knockout or knock-in mouse models, facilitating precise genetic manipulations. The Ggt1 gene, which exhibits specific expression in proximal tubular epithelial cells (TECs) of the kidney, has been extensively employed as a Cre driver for tissue-specific gene targeting within these cells. In this study, to achieve conditional Fam134b knockout in proximal TECs, we generated Fam134b floxed mice and crossed them with Ggt1-Cre transgenic mice. After several generations of selective breeding, we successfully obtained conditional Fam134b knockout mice, which displayed specific deletion of the target gene in proximal TECs. This was confirmed by western blot analysis, which demonstrated a marked deficiency of the FAM134B protein in the renal cortex of these mice. During the mating experiments, we unexpectedly found that we could obtain systematic Fam134b knockout mice, suggesting that Ggt1-Cre might be expressed and functional in germ cells. Genomic and transcriptomic sequencing analysis unequivocally confirmed the deletion of exon 4, while western blot analysis revealed complete absence of FAM134B protein in both heart and kidney tissues of these knockout mice. Through the implementation of different mating strategies, we determined that Ggt1-Cre mediated gene knockout occurs in germ cells that have completed the first meiotic division, rather than in germ cells prior to this developmental stage. Furthermore, qPCR and western blot analyses demonstrated the expression of Cre driven by the Ggt1 promoter in both testes and ovaries, providing additional evidence for its germline activity. Lineage tracing experiments revealed that Ggt1-Cre is expressed in both the kidneys and testes of B6-G/R f/+; Ggt1-Cre transgenic mice, where it effectively catalyzes Cre recombinase activity, leading to the conversion of green fluorescent protein-expressing cells to red fluorescent protein-expressing cells. These findings collectively highlight that Ggt1-Cre is not only a reliable proximal TEC-specific Cre driver but also an effective germline-specific Cre driver. Consequently, it can be utilized to achieve gene knockout or overexpression in both proximal TECs and post-first meiotic division germ cells, thereby enabling in-depth in vivo functional studies of genes in these distinct cell types.

This research intends to explore the molecular mechanism by which Zn alleviates septic AKI in pregnant mice, with a focus on the gut-kidney axis. A septic AKI model was established in non-pregnant and pregnant mice using the cecal ligation and puncture (CLP) method. The changes in serum Zn over time after modeling were observed. Mice were administered with varying doses (low, medium, and high) of zinc gluconate via gavage, subjected to MTF1 knockdown or overexpression, or treated with the PINK1 activator PARL-IN-2, the autophagy inhibitor chloroquine, or the ferroptosis inhibitor Ferrostatin-1. Following these interventions, pathological changes in kidney and intestinal tissues, intestinal barrier function, abundance of specific gut microbiota, and mitophagy and ferroptosis in kidney tissues were assessed accordingly. In CLP-induced septic pregnant mice, serum Zn was depleted. These changes coincided with significant pathological changes in kidney tissue, the intestinal barrier disruption, dysbiosis of the specific gut microbiota, repressed mitophagy, and enhanced ferroptosis. Zn treatment partially ameliorated the kidney injury, activated the MTF1/Nrf2 pathway, restored intestinal barrier function and specific gut microbiota abundance, activated PINK1/Parkin and mitophagy, and restrained ferroptosis. Mechanistic experiments validated that Zn could activate the MTF1/Nrf2 axis, restore the balance of specific gut microbiota abundance, and activate PINK1/Parkin/mitophagy through the gut-kidney axis to alleviate ferroptosis and ameliorate septic AKI in pregnant mice. Zinc ameliorates sepsis-induced AKI in pregnant mice by activating PINK1/Parkin-mediated mitophagy through the MTF1/Nrf2-gut-kidney axis, thereby alleviating ferroptosis and preserving kidney function.

Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (atg5-/-) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80+ macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of atg5-/- macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking Atg5 largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that atg5 deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in atg5-/- RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1.Abbreviations: AKI, acute kidney injury; ATG, autophagy related; Baf, bafilomycin A1; BMDMs, bone marrow-derived macrophages; CCL2/MCP-1, C-C motif chemokine ligand 2; CHX, cycloheximide; CQ, chloroquine; IFNG, interferon gamma; IL, interleukin; IR, ischemia-reperfusion; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MARCHF, membrane associated ring-CH-type finger; NC, negative control; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3, NLR family, pyrin domain containing 3; NOS2, nitric oxide synthase 2, inducible; Rap, rapamycin; Wort, wortmannin; RT-qPCR, real-time quantitative polymerase chain reaction; Scr, serum creatinine; SEM, standard error of mean; siRNA, small interfering RNA; SYK, spleen tyrosine kinase; TARM1, T cell-interacting, activating receptor on myeloid cells 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; TECs, tubule epithelial cells; TNF, tumor necrosis factor; WT, wild type.

Tubular cell death is a hallmark of acute kidney injury (AKI), yet its mechanisms remain unclear. This study elucidates the role of N6-adenosine-methyltransferase-like 3 (METTL3) in renal tubular pyroptosis. METTL3 was upregulated in ischemic AKI models and in hypoxia/reoxygenation (H/R)-treated tubular epithelial cells (TECs). Its silencing alleviated pyroptosis, while overexpression exacerbated it. Conditional METTL3 knockout in mouse TECs attenuated ischemia/reperfusion (I/R)-induced renal injury. Through m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing, we identified TRAF-interacting protein with a forkhead-associated domain (TIFA) as a key target. METTL3 mediates m6A modification of TIFA mRNA, which is recognized by IGF2BP2 to enhance mRNA stability. TIFA promotes NLRP3 transcription via NF-κB signaling, activating the NLRP3 inflammasome and Caspase-1, thereby driving pyroptosis. Targeting METTL3 with tetrahedral framework nucleic acid-delivered siRNA reduced TIFA expression, mitigated renal dysfunction, and suppressed pyroptosis, highlighting the METTL3/TIFA/NLRP3 axis as a potential therapeutic target for AKI.

Autophagy is a conserved degradation process dependent on lysosomes and is essential for maintaining homeostasis in eukaryotic cells. Dysfunctional autophagy can lead to the development and progression of kidney diseases, although the precise mechanisms remain to be completely understood. Recent studies have demonstrated that damaged organelles and long-lived proteins can be selectively identified and degraded via the autophagy-lysosome pathway, a process known as selective autophagy. This process is mediated by various molecules, including sensors, adaptors, and autophagy receptors, and can occur through both ubiquitin-dependent and -independent pathways. Selective autophagy is classified based on the specific substrates targeted for degradation, including mitophagy (mitochondria), pexophagy (peroxisomes), lysophagy (lysosomes), ER-phagy (endoplasmic reticulum), lipophagy (lipid droplets), aggrephagy (protein aggregates), ferritinophagy (ferritin), and other organelle-specific forms. These pathways are recognized as being closely involved in the pathophysiology of various kidney diseases. Modulating selective autophagy through traditional Chinese medicine or compounds, such as autophagosome-tethering compounds, presents a promising therapeutic approach for renal disorders. This narrative review summarizes recent advancements in understanding the molecular mechanisms linking selective autophagy to kidney diseases and explores emerging therapies that target these pathways to enhance clinical outcomes.

Background: Chronic cadmium exposure can induce the onset and progression of hepatorenal fibrosis; however, its molecular basis is unclear. Insulin-like growth factor-binding protein 7 (IGFBP7) is not only a biomarker of acute kidney injury (AKI), but also plays a functional role in promoting kidney injury and inflammation. Abnormal repair of AKI causes kidney fibrosis and chronic kidney disease. IGFBP7 has also been reported as a more sensitive biomarker for liver fibrosis. However, its role in hepatorenal fibrosis requires further investigation. Methods: IGFBP7 global and conditional knockout mice were used to determine the role of IGFBP7 in cadmium-induced hepatorenal fibrosis. Then, liquid chromatography-mass spectrometry, truncated mutants, co-immunoprecipitation, and microscale thermophoresis were employed to unravel the downstream mechanisms. Results: IGFBP7 expression was significantly elevated in kidney and liver tissues of mice subjected to chronic cadmium exposure. IGFBP7 deficiency attenuated cadmium-induced hepatorenal dysfunction and fibrosis, whereas restoration of IGFBP7 expression in IGFBP7-deficient mice reproduced hepatorenal fibrosis. Mechanistically, IGFBP7 interacted with alpha-enolase (ENO1) and inhibited its ubiquitination and degradation. Upregulated ENO1 further promoted glucose metabolic reprogramming and lactate accumulation. Conversely, lactate accumulation enhanced IGFBP7 transcription and expression through histone H3K18 lactylation. Importantly, therapy targeting IGFBP7 significantly ameliorated cadmium-induced hepatorenal fibrosis. Conclusions: IGFBP7 promoted cadmium-induced hepatorenal fibrosis by enhancing ENO1-driven abnormal glycolysis and lactate accumulation.

Environmental and industrial Pb exposure poses a significant public health challenge. Acute exposure to high Pb concentrations can result in renal injury. Here, we revealed that N6-methyladenosine (m6A) RNA methylation was significantly upregulated in lead nephropathy and was mainly mediated by the methyltransferase METTL3. Functionally, METTL3 knockout in renal tubular epithelial cells or AAV9-mediated METTL3 silencing alleviated renal injury and the inflammatory response induced by lead acetate. METTL3 silencing in renal tubular epithelial cells reduced both m6A RNA methylation and inflammatory responses following lead acetate treatment. We identified hexokinase domain-containing 1 (HKDC1), known to function in the glycolytic pathway, as a direct METTL3 target. Importantly, HKDC1 was upregulated at both mRNA and protein levels after lead acetate treatment, thereby promoting renal injury and inflammation. Mechanistically, HKDC1 binds to ATPB and antagonizes the ubiquitinase Murf1, thereby leading to increased expression of ATPB and activation of the NF-κB signaling pathway, which promotes renal inflammation. We further confirmed that STM2457, an inhibitor of METTL3, protected against renal injury and inflammation induced by lead acetate. Collectively, our study demonstrated that the METTL3/HKDC1 axis is a potential target for the treatment of lead nephropathy, and STM2457 is expected to be a protective agent against renal injury caused by lead acetate.

De novo peptide sequencing is a fundamental computational technique for ascertaining amino acid sequences of peptides directly from tandem mass spectrometry data, eliminating the need for reference databases. Cutting-edge models usually encode the observed mass spectra into latent representations from which peptides are predicted autoregressively. However, the issue of missing fragmentation, attributable to factors such as suboptimal fragmentation efficiency and instrumental constraints, presents a formidable challenge in practical applications. To tackle this obstacle, we propose a novel computational paradigm called Latent Imputation before Prediction (LIPNovo). LIPNovo is devised to compensate for missing fragmentation information within observed spectra before executing the final peptide prediction. Rather than generating raw missing data, LIPNovo performs imputation in the latent space, guided by the theoretical peak profile of the target peptide sequence. The imputation process is conceptualized as a set-prediction problem, utilizing a set of learnable peak queries to reason about the relationships among observed peaks and directly generate the latent representations of theoretical peaks through optimal bipartite matching. In this way, LIPNovo manages to supplement missing information during inference and thus boosts performance. Despite its simplicity, experiments on three benchmark datasets demonstrate that LIPNovo outperforms state-of-the-art methods by large margins. Code is available at https://github.com/usr922/LIPNovo.

Background:Acute kidney injury (AKI) involves complex inflammatory responses in which macrophage dysfunction plays a central role. Although histone acetyltransferase KAT2A has been implicated in immune regulation, its role in macrophage ferritinophagy during AKI remains unclear. Methods:Single-cell RNA sequencing analysis of mouse kidney tissue identified abnormal activation of ferritinophagy and upregulation of KAT2A in renal macrophage during AKI progression. Colocalization of FTH1 and LAMP1 and the increased fluorescence intensity of FTH1 and NCOA4 proteins, and KAT2A proteins in macrophage of kidney in AKI samples were detected via immunofluorescence staining. Functional impacts of KAT2A on macrophage ferritinophagy were assessed using KAT2A knockdown and overexpression plasmids in RAW264.7 cell lines. Butyrolactone 3 (MB-3), a specific KAT2A inhibitor, was administered via intraperitoneal injection 24 hours post-IR to assess the influence of MB-3 on renal pathological changes and the activity of macrophage ferritinophagy. Results:In this study, using single-cell RNA sequencing and dual immunofluorescence, we observed aberrant ferritinophagy in renal macrophages, marked by increased colocalization of FTH1 with LAMP1 and NCOA4, alongside elevated CD68 expression. KAT2A was upregulated in macrophages from both human AKI biopsies and murine models. Genetic knockdown of KAT2A suppressed ferritinophagy, reduced NCOA4 and FTH1 expression, decreased FTH1-LAMP1 colocalization, and inhibited cGAS signaling. Conversely, KAT2A overexpression exacerbated these processes. Critically, NCOA4 silencing abolished KAT2A-driven ferritinophagy and cGAS-STING activation. Pharmacological inhibition of KAT2A with MB-3 significantly attenuated renal injury, macrophage infiltration, and ferritinophagy, and reduced colocalization of KAT2A or NCOA4 with F4/80. Conclusion:These findings demonstrate that KAT2A promotes AKI progression via NCOA4-mediated ferritinophagy and cGAS-STING inflammatory signaling in macrophages, highlighting KAT2A inhibition as a promising therapeutic strategy for AKI.

Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.

Chronic kidney disease (CKD) affects more than 10% of the global population, and its incidence is increasing, partially due to an increase in the prevalence of disease risk factors. Acute kidney injury (AKI) is an independent risk factor for CKD and end-stage renal disease (ESRD). The pathogenic mechanisms of CKD provide several potential targets for its treatment. However, due to off-target effects, conventional drugs for CKD typically require high doses to achieve adequate therapeutic effects, leading to long-term organ toxicity. Therefore, ideal treatments that completely cure the different types of kidney disease are rarely available. Several approaches for the drug targeting of the kidneys have been explored in drug delivery system research. Nanotechnology-based drug delivery systems have multiple merits, including good biocompatibility, suitable degradability, the ability to target lesion sites, and fewer non-specific systemic effects. In this review, the development, potential, and limitations of low-molecular-weight protein–lysozymes, polymer nanomaterials, and lipid-based nanocarriers as drug delivery platforms for treating AKI and CKD are summarized.