Ferroptosis, a key mechanism in acute kidney injury (AKI), is centrally regulated by solute carrier family 7 member 11 (SLC7A11). Studies have shown that the splicing factor LUC7-like 2 (LUC7L2) modulates SLC7A11 in the context of glucose metabolism in cancer cells; however, the potential involvement of this regulatory axis in ferroptosis or renal injury remains unknown. Given the well-established roles of SLC7A11 in ferroptosis, we hypothesize that LUC7L2 may influence renal ferroptosis through SLC7A11 in AKI. Integrated in vitro and in vivo models of cisplatin-induced AKI were established. LUC7L2 expression was modulated by siRNA, plasmid overexpression, and adeno-associated virus 9-mediated knockdown. Ferroptosis was evaluated by cell viability, lipid peroxidation, iron accumulation, glutathione levels, and GPX4 expression. Mechanistic studies included exon-specific splicing assays and RNA immunoprecipitation. Public single-cell RNA sequencing datasets were reanalyzed to define cell–type–specific expression patterns, and the findings were validated in human kidney biopsy specimens and urine samples. The results demonstrate that LUC7L2 expression is upregulated in cisplatin-induced models of AKI. Functionally, it promotes ferroptosis by regulating SLC7A11, thereby reducing glutathione synthesis and exacerbating oxidative stress. We identified a dual-pathway mechanism in which cisplatin-activated p53 represses transcription of SLC7A11, while LUC7L2 post-transcriptionally controls pre-mRNA splicing of SLC7A11 via direct binding and is associated with increased exon skipping. Under cisplatin stress, LUC7L2 is associated with non-productive SLC7A11 splicing and reduced functional SLC7A11, thereby promoting ferroptotic susceptibility. In functional assays, we found that renal ferroptotic injury is attenuated by LUC7L2 knockdown but exacerbated by its overexpression. Taken together, these findings identify LUC7L2 as a contributor to cisplatin-induced AKI through splicing-dependent control of SLC7A11. This study reveals a previously unrecognized post-transcriptional mechanism governing ferroptosis in the kidney and highlights LUC7L2 as a potential diagnostic biomarker and therapeutic target.

Diabetes-related cognitive dysfunction (DCD) represents a significant complication of diabetes mellitus, yet its underlying molecular mechanisms remain incompletely elucidated. In this study, we aimed to investigate the potential role of nuclear receptor coactivator 3 (NCOA3) in DCD pathogenesis using both conditional knockout (cKO) and lentivirus-mediated overexpression mouse models. Diabetes was induced through combined high-fat diet feeding and low-dose streptozotocin (STZ) administration. Comprehensive behavioral assessments, including novel object recognition test (NORT), Y-maze, and contextual fear conditioning (CFC), were performed alongside molecular analyses of NCOA3/AGO2 expression and downstream targets. Our results suggested a significant downregulation of NCOA3 expression in cortical and hippocampal tissues of diabetic mice. Genetic ablation of NCOA3 in forebrain excitatory neurons markedly appeared to exacerbate hippocampus-dependent cognitive deficits, while targeted hippocampal NCOA3 overexpression effectively ameliorated these impairments. At the mechanistic level, NCOA3 deficiency was associated with reduced protein levels of AGO2, along with downregulation of the synaptic markers synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95). In vitro studies using primary neuronal cultures indicated that high glucose treatment similarly reduced the expression of both NCOA3 and AGO2, while pharmacological inhibition or genetic knockdown of NCOA3 was found to significantly upregulate miR-138-5p levels. These findings collectively suggested a potential regulatory axis wherein NCOA3 is associated with synaptic plasticity via AGO2/miR-138-5p signaling, providing insights into DCD pathogenesis.

Lipoprotein glomerulopathy (LPG) is a rare hereditary glomerular disease with lipoprotein thrombi deposition in glomerular capillaries, which is caused by pathogenic variants in APOE gene. Limited research has theoretically suggested that APOE gene mutations might affect sperm quality and contribute to male infertility. However, there have been no reports documenting the occurrence of LPG and male infertility in the same individual worldwide. Herein, we report a 36-year-old slim man who presented with nephrotic syndrome and had abnormal sperm quality. Kidney biopsy confirmed the diagnosis of LPG based on apolipoprotein E (ApoE) deposition. A pathogenic mutation in APOE (c.127C>T; p.Arg43Cys) was discovered by whole-exome sequencing. The patient was sensitive to lipid-lowering treatment, successfully achieving the remission of proteinuria within one month of therapeutic intervention. Furthermore, after four months' treatment the patient's wife conceived naturally and ultimately gave birth to a full-term infant. We highly emphasize the importance of timely renal biopsy and subsequent gene screening in similar clinical cases.

Peritoneal dialysis-associated peritonitis (PDAP) caused by Ureaplasma parvum (U. parvum) is exceedingly rare, and its diagnosis is particularly challenging due to the organism’s biological characteristics and the limitations of conventional detection methods. To date, only sporadic case reports are available, but the diagnostic processes and clinical characteristics of PDAP caused by U. parvum infection have not been comprehensively reported yet. We report a 35-year-old female patient undergoing continuous ambulatory peritoneal dialysis (CAPD) who experienced three episodes of peritonitis within a six-month period. Despite empirical antibiotic therapy leading to clinical improvement, routine microbiological cultures of the dialysate remained negative during each episode. During the third episode, metagenomic next-generation sequencing (mNGS) of the peritoneal dialysis (PD) effluent finally detected U. parvum as the causative pathogen. Following removing a potential risk factor, an intrauterine device (IUD), and adjusting the antimicrobial therapy to intraperitoneal (IP) levofloxacin and oral azithromycin, the patient achieved complete recovery and successfully resumed PD. Based on this experience, we documented the characteristic clinical profile of such infections and proposed an exploratory clinical diagnosis and treatment flowchart. Patients with recurrent culture-negative PDAP, especially female with an IUD, should be evaluated for U. parvum infection as a potential pathogen. mNGS facilitates the rapid detection of pathogens that traditional methods may fail to identify. Effective management of such infections necessitates not only targeted antimicrobial therapy guided by precise pathogen identification, but also the removal of potential risk factors such as the IUD.

Background Chronic kidney disease (CKD) affects approximately 10% of global populations, pathologically characterized by renal fibrosis including extracellular matrix (ECM) deposition and renal tubular atrophy. Emerging evidence suggests that autophagy plays a crucial role in renal fibrosis, but the regulatory mechanisms are still not well understood. Purposes In this study, we try to explore the role of activating transcription factor 3 (ATF3) in renal fibrosis as well as the potential mechanisms. Methods We utilized two CKD mouse models to confirm the expression of ATF3 via immunohistochemistry staining, western blot or real-time quantitative polymerase chain reaction (RT-qPCR). Then, ATF3 knockdown mice were constructed to investigate its impact on renal fibrosis by adeno-associated virus (AAV) administration. Additionally, transcriptomic analyses and in vitro experiments were performed in The Boston University mouse proximal tubular (BUMPT) cell lines to evaluate the possible downstream signaling pathways. Results Our results demonstrated that the expression of ATF3 was significantly increased in kidney specimens from both unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) mice. Knockdown of ATF3 attenuated ECM deposition and epithelial-mesenchymal transition (EMT) in vivo and vitro. Autophagy was indicated to be involved in ATF3-mediated renal fibrosis by transcriptomic analyses, which was verified by genetic deletion of ATF3 in BUMPT cells. Besides, the database indicated that early growth response protein 2 (EGR2), a potent profibrotic molecule proven previously, was suggested to be transcriptionally activated by ATF3, which was partially confirmed by in vitro experiments. Conclusions Collectively, enhanced expression of ATF3 exerts a detrimental effect in renal fibrosis by regulating EGR2-mediated autophagy pathways.

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulopathy globally, exhibits intricate pathomechanisms and significant clinical heterogeneity, with up to 50

BACKGROUND:Acute kidney injury (AKI) is characterized by a rapid decline in renal function and is associated with high mortality worldwide. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, exerts protective effects in AKI, although the underlying mechanisms remain unclear. Exosomes derived from multivesicular bodies (MVBs) play diverse roles in kidney diseases. Emerging evidence suggests that lysosome-dependent degradation of MVBs plays an important role in regulating exosome secretion. Based on this, TFEB may inhibit exosome secretion by promoting lysosomal biogenesis and lysosome-dependent degradation of MVBs, thereby attenuating AKI progression. METHODS:In this study, rat renal tubular epithelial cells (TECs) were treated with cisplatin under TFEB modulation (TFEB siRNA or trehalose), to assess TFEB expression, lysosome-related molecules, exosome secretion, and MVBs dynamics. In vivo, TFEB-overexpressing lentivirus was injected into mouse kidneys followed by cisplatin-induced AKI, and changes in TFEB, lysosomal function, and the MVB-exosome pathway were evaluated. RESULTS:Our results showed that cisplatin promoted the release of pathogenic exosomes from TECs, which in turn damaged neighboring healthy TECs via paracrine effects. In rat TECs, trehalose-induced TFEB upregulation enhanced lysosomal biogenesis and MVB degradation, thereby reducing cisplatin-induced exosome secretion and TEC injury. Similarly, in cisplatin-induced AKI mice, TFEB overexpression alleviated renal damage. Exosome secretion was increased in AKI mice, but this increase was attenuated in mice injected with a TFEB-overexpressing lentivirus. TFEB overexpression led to increased cathepsin D (CTSD) expression, decreased expression of MVB-related proteins, and significantly enhanced MVB-lysosome interaction. CONCLUSION:Cisplatin-induced exosome secretion from TECs promotes injury in neighboring TECs. TFEB protects against cisplatin-induced AKI by enhancing lysosome-dependent degradation of MVBs, thereby reducing pathogenic exosome secretion from TECs and alleviating kidney damage.

Background Diabetic kidney disease (DKD) is a leading cause of kidney failure closely linked to lifestyle factors, but the mechanisms have not been systematically investigated.Aim This study aimed to assess the long-term metabolic effects of lifestyle behaviors on DKD.Design and methods This study aimed to examine links between lifestyle, metabolic biomarkers, and DKD incidence and mortality in a population with diabetes. This study analyzed data from 18 287 participants, evaluating five lifestyle factors (diet, sleep duration, physical activity, smoking and alcohol intake) alongside 251 metabolic biomarkers. Cox proportional hazards models and Mendelian randomization (MR) assessed associations. Mediation analysis was conducted on biomarkers linked to both lifestyle and DKD. Additionally, genome-wide association study (GWAS) and gene enrichment analysis were conducted on mediating biomarkers to explore biological mechanisms.Results Among 18 287 participants with diabetes, 3247 developed DKD over a median follow-up of 14.6 years. Lipids and amino acids were associated with DKD and mediated the effects of lifestyle factors. Mediating biomarkers, including triglycerides to total lipids in HDL percentage and glycoprotein acetyls, demonstrated both observational and causal associations with DKD. The mediation effects differed between various levels of blood glucose control. Pathway enrichment analysis identified both shared and distinct biological pathways.Conclusions This comprehensive study underscores the importance of metabolomics in delineating the mechanisms by which lifestyle behaviors influence DKD, paving the way for targeted interventions.

Acute kidney injury (AKI) is a severe clinical syndrome with high morbidity and mortality, yet its pathogenesis remains incompletely understood, and effective therapeutic strategies are still lacking. In this study, we observed significant upregulation of N-acetyltransferase 10 (NAT10) in the tubular epithelial cells of Cisplatin-induced AKI. Lentivirus-mediated knockdown of NAT10 or treatment with NAT10 inhibitor Remodelin, ameliorated Cisplatin-induced renal dysfunction and tubular injury. Importantly, NAT10 inhibition markedly attenuated cellular senescence in Cisplatin-induced AKI, as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity, downregulation of senescence markers (p53, p21 and γ-H2A.X) and decreased levels of senescence-associated secretory phenotype (SASP) factors (IL-1β, IL-6 and TNF-α). Mechanistically, co-immunoprecipitation assay suggested that NAT10 interacted with DDX17 to regulate its expression. Knockdown or inhibition of NAT10 reduced the protein expression of DDX17 in Cisplatin-injured kidneys. While silencing DDX17 could inhibit Cisplatin-induced senescence in HK-2 cells. Furthermore, we demonstrated that the effects of NAT10 on Cisplatin-induced tubular injury and senescence was dependent on DDX17. Our study revealed a novel mechanism by which NAT10 promoted Cisplatin-induced renal tubular cell senescence via DDX17 upregulation, suggesting that targeting the NAT10/DDX17 signaling axis may offer a potential therapeutic strategy for AKI.

Introduction Murine double minute 2 (MDM2) has been implicated in diverse neurological disorders, yet its precise function in the central nervous system remains poorly defined. Objectives This study aimed to elucidate the roles of MDM2 in postnatal forebrain development, synaptic function, and cognition by generating and analyzing a forebrain-specific conditional knockout (cKO) model. Methods We generated a forebrain-specific conditional knockout mouse line in which MDM2 was selectively ablated under the control of the CaMKIIα promoter. We employed morphometric analysis, Western blot, whole-cell patch-clamp recordings in hippocampal pyramidal neurons, in vivo two-photon calcium imaging in the primary visual cortex, and behavioral tests (Y-maze, novel object recognition, Morris water maze) to assess memory and learning. Results MDM2 cKO mice exhibited severe microcephaly, characterized by cortical thinning, hippocampal shrinkage, and reduced neuronal density alongside glial proliferation. Synaptic deficits were evident from reduced synaptic protein levels, dendritic spine loss, and impaired long-term potentiation. Moreover, MDM2-deficient neurons showed intrinsic hyperexcitability. In vivo calcium imaging revealed normal mean response to visual stimulus but impaired cortical computation, with reduced population coding capacity for naturalistic stimuli. Behaviorally, MDM2 cKO mice displayed profound deficits in spatial memory, object recognition, and spatial learning. Conclusions Our findings establish MDM2 as a critical regulator of postnatal cortical structure, synaptic plasticity, and cognitive function, highlighting its potential as a therapeutic target for neurodevelopmental disorders with cognitive deficits.

Hypertension-induced renal injury is a major cause of chronic kidney disease and end-stage renal disease. Increasing evidence indicates that disease progression is not driven solely by hemodynamic stress but results from the interplay of multiple molecular mechanisms. In this review, we propose a stage-structured and network-based framework to systematically integrate current mechanistic insights into hypertension-induced renal injury. Early events, mainly including endothelial dysfunction and renal hypoxia, establish a permissive microenvironment for disease progression. These insults activate amplifying pathways such as the renin-angiotensin-aldosterone system (RAAS) overactivation, oxidative stress, immune and inflammatory responses, and sympathetic nervous system hyperactivity, which interact through cross-talk and positive feedback loops. Ultimately, these signals converge on fibrotic programs characterized by epithelial-mesenchymal transition (EMT), fibroblast activation, and extracellular matrix deposition, leading to irreversible structural remodeling and functional decline. Furthermore, epigenetics, the gut-kidney axis, autophagy dysfunction and renal aging also contribute to this process. We highlight two critical and underappreciated aspects: the existence of a permissive 'early-window' dominated by endothelial dysfunction and hypoxia, which sets the stage for later amplification; and the hierarchical interplay between amplifying mechanisms where cross talk creates self-reinforcing loops that may explain therapeutic resistance. In addition, this review highlights emerging biomarkers for early diagnosis and disease monitoring, and discusses therapeutic advances that extend beyond blood pressure control to disease-modifying interventions that confer renoprotective effects. By integrating molecular mechanisms with diagnostic and therapeutic perspectives, this review provides a comprehensive framework for early detection and precision intervention in hypertension-induced renal injury.

Podocyte injury and detachment are early cellular events in hypertensive nephropathy, yet their underlying mechanisms are not well clarified. Zyxin, a mechanotransducer located at focal adhesions, regulates actin cytoskeleton remodeling and exhibits diverse biological functions. However, its role in podocytes is poorly understood. In this study, we constructed a hypertensive nephropathy model in podocyte-specific zyxin knockout mice to explore the role of zyxin in hypertensive conditions. In vitro, mechanical stretch and Angiotensin II (AngII) were used to stimulate podocytes. Western blot, real-time PCR, and immunofluorescence were performed to underscore underlying mechanisms. We identified decreased zyxin levels in the glomeruli of a hypertensive nephropathy mouse model. Mechanical stretch and AngII altered zyxin expression and distribution in podocytes. Moreover, podocyte-specific zyxin knockout worsened hypertension-induced renal dysfunction, glomerulosclerosis, glomerular basement membrane thickening, foot process effacement, and podocyte loss. Zyxin knockdown disrupted the actin cytoskeleton, accompanied by reduced α-actinin-4 expression and changes in focal adhesion proteins, including vinculin and paxillin, which may contribute to altered podocyte motility and adhesion. These findings indicate that zyxin is involved in the regulation of podocyte cytoskeletal organization and cell behavior, likely through coordinated effects on multiple cytoskeletal and focal adhesion-related pathways rather than a single downstream mediator. In this context, zyxin may play a protective role in maintaining podocyte stability during hypertensive nephropathy.

Arteriovenous fistula (AVF) maturation is characterized by outward remodeling presented mainly as wall thickening and lumen enlargement, probably mediated by increased differentiated vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) deposits, at least in part. Our previous study revealed that the highly conserved transcription factor early growth response protein 2 (EGR2) promoted renal tubular epithelial cell differentiation and ECM accumulation. Here, we found that EGR2 expression was enhanced in venous outflow tracts from end-stage renal disease (ESRD) patients and mice with AVF surgery accompanied by a thickened venous wall and enlarged lumen. Then, the knockdown of EGR2 could inhibit AVF maturation while EGR2 overexpression further promoted outward remodeling in AVF mice with adeno-associated virus (AAV) administration regulated by differentiated VSMCs and ECM deposition. Mechanistically, gene deletion of EGR2 inhibited c-Myc possibly by binding to the promoter region of the insulin-like growth factor 2 binding protein 2 (IGF2BP2) gene. Moreover, EGR2 was upregulated by histone deacetylase 4 (HDAC4) which probably negatively regulated transcription factor c-Jun, the latter was reported to antagonize the effect of EGR2. Thus, we speculated that EGR2 is upregulated by HDAC4 possibly by negatively regulating c-Jun and promoting outward remodeling through the IGF2BP2/ c-Myc signaling axis during AVF maturation.

Abstract. Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide, characterized by increasing prevalence and limited therapeutic options. This review comprehensively synthesizes recent advances in the molecular mechanisms underlying DKD progression, focusing on key cellular events including podocyte injury, tubular damage, endothelial dysfunction, pericyte loss, and immune-inflammatory responses that drive glomerular and tubulointerstitial fibrosis. We further elaborate on critical pathways such as lipotoxicity, mitochondrial dysfunction and oxidative stress, aberrant autophagy, inflammasome activation, and profibrotic signaling. The review also highlights clinically approved agents including renin–angiotensin–aldosterone system inhibitor, sodium-glucose cotransporter 2 inhibitors, endothelin receptor antagonists, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, and emerging therapeutic targets and agents currently under preclinical and clinical investigation, including anti-inflammatory, anti-fibrotic, and metabolic interventions. By integrating mechanistic insights with translational evidence, this work aims to provide a comprehensive review for the development of DKD.

The onset and progression of chronic kidney disease (CKD) are closely associated with persistent inflammatory responses, oxidative stress imbalance, and macrophage dysfunction; however, therapeutic strategies capable of multidimensionally regulating the inflammatory microenvironment remain limited. In this study, we constructed a biomimetic nanodecoy, PBP@Anti@M2c, based on black phosphorus nanosheets. By integrating the outstanding reactive oxygen species (ROS)-scavenging capability of black phosphorus nanosheets, the cholesterol metabolism-regulatory function of Anti-miR-33, and the inflammation-targeting and cytokine-sequestering properties of M2c macrophage membranes, this platform enabled synergistic intervention in the CKD inflammatory microenvironment. This nanosystem not only efficiently eliminated excessive ROS and suppressed inflammatory cytokine release, but also upregulated the cholesterol efflux transporters ABCA1 and ABCG1 by inhibiting miR-33, thereby promoting macrophage lipid metabolic reprogramming and inducing polarization toward the M2c phenotype, which in turn enhanced efferocytosis and accelerated inflammation resolution. In both UIRI and UUO mouse models of CKD, PBP@Anti@M2c markedly alleviated renal oxidative stress and inflammation, inhibited the progression of renal interstitial fibrosis, and exhibited favorable in vivo biosafety. This study proposes a metabolism-immunity dual-dimensional regulatory strategy based on the inflammatory microenvironment and provides a new therapeutic concept for CKD.

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, despite therapeutic advances. Podocyte injury constitutes a critical pathogenic process in DKD. This study elucidated the role of the neonatal Fc receptor (FcRn) in DKD-associated podocyte injury. In DKD, glomerular FcRn expression was markedly elevated and inversely correlated with podocin levels. In diabetic mice, podocyte-specific FcRn deficiency significantly ameliorated insulin resistance and mitigated podocyte damage. Mechanistically, FcRn upregulation in diabetic podocytes exacerbated insulin resistance, suppressed AKT/mTOR signaling, and impaired autophagy, thereby promoting podocyte injury. These findings identify FcRn as a pivotal contributor to podocyte injury in DKD and suggest that FcRn targeting represents a promising therapeutic strategy. Article Highlights Neonatal Fc receptor (FcRn) mediates podocyte injury in immune complex nephropathies, but its role in diabetic kidney disease (DKD) remains undefined. This study demonstrates marked FcRn upregulation in DKD podocytes and elucidates the functional consequences of podocyte FcRn deficiency. FcRn deficiency protects podocytes in DKD by restoring autophagy via enhanced insulin sensitivity and subsequent AKT/mTOR signaling activation. These findings identify FcRn as a novel therapeutic target for DKD, offering a strategy to mitigate the substantial residual risk of disease progression despite current therapies.

Renal aging involves structural and functional kidney decline (reduced size/nephrons, glomerulosclerosis, tubular atrophy, functional loss) and is an independent risk factor for kidney and systemic degenerative diseases. On 16 May 2025, the Aging Biomarker Consortium convened an expert consensus meeting in Shanghai, proposing a multidimensional biomarker framework: functional (estimated glomerular filtration rate, renal blood flow), structural (renal volume loss), and humoral (Klotho, N-terminal Pro-B-type natriuretic peptide, senescence-associated secretory phenotype factors). The consensus also supports machine-learning models for biological age assessment and calls for multi-center cohorts and translational collaboration to improve elderly kidney health.

Background: Although the World Health Organization no longer classifies coronavirus disease 2019 (COVID-19) as a global health emergency, its long-term sequelae continue to affect survivors physically, psychologically, and socially. Summary: This review focuses on a vulnerable population – patients receiving kidney replacement therapy (KRT) – and summarizes their COVID-19-associated epidemiological characteristics, clinical manifestations, clinical outcomes, interventions, and vaccination challenges. Key Messages: KRT patients faced markedly higher severe acute respiratory syndrome coronavirus 2 infection risks, atypical clinical presentations, and high mortality rates. Specialized management strategies for patients on KRT were recommended. COVID-19 vaccination formed the cornerstone of controlling COVID-19 but also raised concerns over its long-term safety and immunogenicity profiles.