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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2025 Oct 28;50(10):1900–1914. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2025.250245

Klotho蛋白在慢性肾脏病中的早期诊断与靶向治疗潜力

Potential of early diagnosis and targeted therapy for Klotho protein in chronic kidney disease

LI Yifeng 1,2, CHEN Guihong 1, CHEN Meijun 1, LIN Yan 1, LUO Cheng 1, GUO Lingxin 1, HU Wenbao 1, LIU Zhengzhao 1,2,✉
Editor: 吴 旭芳
PMCID: PMC12949869  PMID: 41656819

Abstract

Klotho (KL) protein is a key renoprotective protein that exerts organ-protective effects through regulation of mineral metabolism, anti-inflammatory and antioxidant activity, anti-aging signaling, modulation of autophagy, and inhibition of fibrosis. KL levels decline from the early stage of chronic kidney disease (CKD) and are correlated with disease severity, indicating its strong potential as an early diagnostic biomarker. However, current KL-targeted therapies have not yet achieved clinical translation. Recent studies demonstrate that engineered fibroblast growth factor-23 (FGF-23) binding peptides show up to a 2 300-fold increase in affinity for KL, providing a basis for developing high-sensitivity KL assays. In parallel, persistent activation of endoplasmic reticulum (ER)-associated degradation (ERAD) may represent a major mechanism driving KL ubiquitination and degradation. The emerging deubiquitinase-targeting chimera (DUBTAC) technology protects target proteins from degradation by inhibiting their ubiquitination. The combination of engineered FGF-23 binding peptides and KL-targeted DUBTAC technology may accelerate clinical development of sensitive detection and targeted therapeutic strategies for KL, holding substantial clinical significance for CKD management.

Keywords: Klotho, chronic kidney disease, biomarkers, protein degradation, endoplasmic reticulum-associated degradation

慢性肾脏病(chronic kidney disease，CKD)是指肾脏结构异常或功能减退持续3个月及以上的病理状态[1]，包括出现肾脏损伤标志、尿沉渣异常、组织或影像学异常，可能由高血压、糖尿病、慢性肾小球肾炎或多囊肾病等多种因素引起。随着生活方式的变化和人口老龄化，CKD的发病率逐年攀升，已成为全球范围内的重大公共卫生问题，大大增加了患者和社会负担[2-3]。在CKD管理中，调整生活方式和药物干预有助于缓解病情，但中晚期阶段患者常需依赖血液透析、腹膜透析甚至肾脏移植来维持基本的代谢功能。早期筛查CKD和加速新型药物开发刻不容缓。

克老素(Klotho，KL)基因是由Kuro-o等[4]于1997年发现的一种抗衰老和肾脏保护基因。KL发挥着肾脏保护、调节钙磷代谢、延缓肾病进展、改善心血管功能、抗癌、抗炎和抗氧化等作用。敲除KL的小鼠仅能存活2个月，过表达KL可延长寿命30%[4]。截至2025年9月23日，全球已注册112项KL相关的临床试验(数据来源：https://clinicaltrials.gov/)，涵盖肾病[如CKD、急性肾损伤(acute kidney injury，AKI)、肾移植、肾结石]、骨代谢异常(如骨关节炎、低磷血症佝偻病)及代谢性疾病(如糖尿病、肥胖)等多领域，研究聚焦于KL蛋白水平与疾病关联性，以及药物、运动等干预对其表达和疾病状态的影响。近年来的临床研究[5-6]表明：KL蛋白和CKD的发生和预后相关，且在多种肾脏病中的表达下调，逐渐成为临床治疗CKD的新靶点。但是靶向KL的CKD诊断和治疗方法仍未进入临床应用，新技术如去泛素化酶靶向嵌合体(deubiquitinase-targeting chimera，DUBTAC)的发展或将为CKD患者带来新的曙光。

1. KL的基因编码和蛋白质结构

KL基因定位于人类第13号染色体，包含2个转录本。其中，全长转录本由5个外显子组成，编码135 kD(1 D=1 u)的单次跨膜蛋白，主要在肾、脉络丛、大脑、垂体和甲状旁腺中表达[7]。在肾脏中，Nephroseq v5数据库的转录组学和临床数据[8]显示KL主要在肾小管间质中表达。

相应地，KL蛋白可分为膜结合型KL(membrane-bound KL，mKL)、可溶型KL(soluble KL，sKL)和分泌型KL(secreted KL，seKL)3种亚型。人源mKL是单次跨膜蛋白，全长1 012 个氨基酸(amino acid，AA)，包括N端信号序列(signal sequence，SS；1~33 AA)、胞外结构域(1~981 AA)、跨膜(transmembrane，TM)结构域(982~1 002 AA)和短胞质尾(cytoplasmic tail，CYT；1 003~1 012 AA)(图1)。胞外结构域含KL1(56~506 AA)和KL2(515~953 AA)2个结构域，与β-葡萄糖苷酶(β-glucosidase)高度同源。因此，KL蛋白对葡萄糖醛酸化类固醇表现出较弱的糖苷酶活性，但由于239和872位缺少必要的活性位点谷氨酸残基，在体内无糖苷酶活性。解整合素和金属蛋白酶(a disintegrin and metalloproteinase，ADAM)负责切割mKL使sKL释放，含有SS、KL1和KL2的胞外结构域可被ADAM10或者ADAM17切割，释放130 kD的sKL到循环系统中，或被切割成单独的68 kD(KL1+SS)和64 kD(KL2)的蛋白质[9]。此外，KL的选择性剪接可产生仅含KL1结构域的seKL(约70 kD)。这种可变剪切产生的seKL与全长序列的差别仅在于增加了15个特异序列AA[10](图1)。

图1.

图1

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KL蛋白的结构和作用机制

Figure 1 Structure and mechanism of action of KL protein

KL: Klotho; mKL: Membrane-bound KL; sKL: Soluble KL; AA: Amino acid; SS: Signal sequence; TM: Transmembrane; CYT: Cytoplasmic tail; FGF-23: Fibroblast growth factor-23; FGFR: Fibroblast growth factor receptor; ADAM: A disintegrin and metalloproteinase; mRNA: Messenger RNA.

2. KL的生理功能

2.1. 维持骨矿物质代谢平衡

成纤维细胞生长因子23(fibroblast growth factor-23，FGF-23)是一种重要的骨骼激素，于2000年首次在大脑的腹外侧丘脑核中被发现，是成纤维细胞生长因子家族的新成员[11]。其受体包括成纤维细胞生长因子受体(fibroblast growth factor receptor，FGFR) 1C/3C/4。KL通过抑制磷酸盐再吸收和激活FGF-23来调节体内磷酸盐的平衡[12]。在肾脏中，mKL是肾小管上皮细胞表达KL的主要形式，其作为FGF-23与其主要受体FGFR1C结合的辅助因子发挥作用[13]。

KL是FGF-23与FGFR1高亲和力结合所必需的因子(图1)。FGFR的胞外结构域由3个免疫球蛋白样结构域组成，即D1、D2和D3，其中D2、D3和D2-D3连接子的膜近端部分对与FGF配体结合至关重要。FGF-23结合在FGFR受体的D2和D3结构域之间。同时，在KL、FGF-23和FGFR形成的三元复合物中，KL蛋白的KL2结构域形成1个大的结合袋，锚定FGF-23的远端C端尾部[14]。KL通过受体结合臂(receptor-binding arm，RBA)结构与FGFR1相互作用并改变其构象[15]，使FGFR1与FGF-23紧密结合并激活下游丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)信号通路。FGFR激活通过近端肾小管中的磷酸钠协同转运蛋白2a/2c，减少无机磷酸盐的重吸收[16]，在远端小管中，通过TRPV5通道增强Ca2+的重吸收。

FGF-23与维生素D、甲状旁腺激素共同维持肾脏钙磷平衡。FGF-23具有双重机制：一方面，通过降低磷酸钠协同转运蛋白的细胞表面表达和抑制肾脏中维生素D生物合成的限速酶转录来调节磷酸盐和维生素D稳态[14]；另一方面，通过抑制1α-羟化酶，降低活性维生素D[1, 25-(OH)2D3]的合成，同时刺激24-羟化酶的表达，促进生成骨钙化醇[1, 24, 25-(OH)3D3]使活性维生素D失活，抑制钙的吸收[17]。

近期研究[14]发现：除mKL外，sKL也可作为FGF-23的辅助受体，其可溶性和跨膜形式具有相似的支持FGF-23信号转导的能力，向野生型小鼠注射sKL会导致肾磷酸盐排泄增加和血清磷酸盐减少。

2.2. 抗炎、抗氧化、抗衰老、调节自噬和抗纤维化

在肾脏中，mKL在肾小管上皮细胞基底侧经分泌酶ADAM切割后释放入血液循环，形成sKL，后者是循环中的主要功能形式。sKL作为内分泌或旁分泌因子，通过影响多条信号通路发挥广泛的生理作用(图1)。

sKL通过上调白细胞介素-10(interleukin-10，IL-10)，抑制肿瘤坏死因子-α(tumor necrosis factor-alpha，TNF-α)诱导的核因子-κB(nuclear factor-κB，NF-κB)通路激活，减少多种促炎性细胞因子的产生[18]。sKL还可激活核因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)，通过减少活性氧(reactive oxygen species，ROS)和炎症因子的产生，参与肾脏细胞的抗氧化反应[19-20]。KL作为一种抗衰老蛋白，其表达水平随年龄的增长而下降[21]。肾小管特异性KL敲除小鼠呈现系统性衰老表型，表明肾脏中产生的KL具有重要的抗衰老功能[22]。KL表达下调会增加p53、p21及p16INK4a的表达，加速肾脏细胞衰老[23]。此外，KL可以增加肾脏微管相关蛋白轻链3(light chain 3，LC3)II/I水平，促进转录因子EB(transcription factor EB，TFEB)核易位并增加TFEB介导的溶酶体基因转录，促进自噬[24]。在高糖条件下，KL表达的下调会抑制近端肾小管细胞的自噬活性[25]。KL还通过抑制转化生长因子-β1(transforming growth factor-beta 1，TGF-β1)/SMAD家族成员3(SMAD family member 3，Smad3)[26]和无翅型MMTV整合位点家族(wingless-type MMTV integration site family，Wnt)/β-连环蛋白[27]信号通路，下调α-平滑肌肌动蛋白和纤连蛋白的表达，从而发挥抗纤维化作用。

KL是重要的肾脏保护蛋白，其缺乏既是CKD进展的病理标志，也是CKD的驱动因素。在肾损伤的单侧输尿管梗阻(unilateral ureteral obstruction，UUO)或者单侧缺血再灌注损伤(unilateral ischemia-reperfusion injury，UIRI)模型中，KL表达显著下调；在各种CKD模型中，提高肾脏KL水平可预防肾病并减轻肾纤维化[27]。KL通过多机制发挥肾脏保护作用：1)在AKI阶段，通过抑制氧化应激、炎症反应和NF-κB/NOD样受体热蛋白结构域相关蛋白3通路介导的细胞焦亡保护肾脏[23]；2)在糖尿病肾病(diabetic nephropathy，DN)中，通过阻断TGF-β1/Smad3信号通路下调早期生长反应-1(early growth response-1，Egr-1)表达，同时抑制NF-κB和TGF-β1信号转导，从而减轻肾脏炎症和纤维化[24]；3)在肾移植方面，通过抑制上皮-间充质转化(epithelial-mesenchymal transition，EMT)进程，有效延缓肾同种异体移植物纤维化和慢性移植功能障碍的发生、发展[25]。这些发现共同表明：KL通过其抗炎、抗氧化和抗纤维化作用，在从AKI到CKD的全疾病谱中发挥系统性保护效应。

3. CKD中的KL下降机制及并发症

3.1. CKD中KL下降的机制

在CKD中，KL表达下调的机制可分为上游表观遗传调控和下游蛋白稳态失衡两方面。上游机制方面，炎症、氧化应激、肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system，RAAS)激活和异常代谢(如高磷血症和尿毒症)都会导致KL的表达降低[28-29]，其特点是KL启动子甲基化或组蛋白乙酰化等导致的转录水平降低，使KL生成减少。KL启动子是一个CpG岛，包含高频率的GC序列，可以被高度甲基化，在KL的时空特异性和疾病中的表达起重要作用，DNA去甲基化剂使非表达细胞中的KL表达增加1.5~3.0倍[30]。这可能解释了在各种病因的CKD模型中，肾脏mKL表达抑制与KL启动子甲基化程度的相关性。最近研究[31]发现：UUO模型中，上调的炎症标志物C-C基序趋化因子5(C-C motif chemokine ligand 5，CCL5)通过激活信号转导和转录激活因子3(signal transducer and activator of transcription 3，STAT3)，诱导了DNA甲基转移酶1(DNA methyltransferase 1，DNMT1)介导的KL启动子甲基化，揭示了CCL5/p-STAT3/DNMT1这一新型上游机制。

相应地，下游机制的破坏(如KL的异常修饰、易位和降解)也可能在CKD中起关键作用。CKD状态下，白蛋白尿[32]及RAAS激活[33]介导的持续性内质网(endoplasmic reticulum，ER)应激[34]可能导致胞内KL错误折叠，并通过ER相关蛋白降解(ER-associated degradation，ERAD)通路被泛素-蛋白酶体系统(ubiquitin-proteasome system，UPS)降解[35]。ERAD及ER应激的特异性抑制显著恢复了mKL和sKL水平，但未恢复其信使RNA(messenger RNA，mRNA)水平，提示CKD中KL的下降存在下游机制调节的可能性[32, 36]。最新研究[36]表明：UUO模型小鼠KL下降并伴随着ER应激标志物上升，同时注射ERAD抑制剂(eyarestatin I)通过未折叠蛋白反应增加了sKL水平，提示ERAD可能是调控KL的新型下游机制。

3.2. KL下降与CKD并发症

FGF-23和sKL在肾脏中的联合作用对磷酸盐和维生素D的代谢至关重要[37]，sKL通过分子相互作用抑制FGF-23效应[38]。在CKD早期，KL表达的降低可导致FGF-23的过量产生，从而引起继发性甲状旁腺功能亢进，这是CKD患者的常见并发症[39]。在一项病例队列研究[40]中，CKD患者的FGF-23水平与骨折发生率呈线性相关，而KL、甲状旁腺激素(parathyroid hormone，PTH)和磷酸盐水平与之呈U形关联。

慢性肾脏病矿物质和骨异常(chronic kidney disease-mineral and bone disorder，CKD-MBD)始于CKD 2期，与KL缺乏密切相关，而恢复KL水平有利于CKD-MBD的改善[6, 41]。血管钙化(vascular calcification，VC)作为CKD-MBD的重要组成部分，是CKD患者心血管事件和死亡的主要危险因素之一，与非动力性骨病密切相关，其特征是骨形成减少或缺失、成骨细胞和破骨细胞的含量降低[42]。CKD小鼠的KL缺乏引起VC，而sKL可抑制钠依赖性摄取磷酸盐和磷酸盐诱导的大鼠VC的进展[43]。哺乳动物雷帕霉素靶标蛋白(mammalian target of rapamycin，mTOR)信号在CKD大鼠主动脉壁中被激活，而口服雷帕霉素通过mTOR上调血管的mKL，显著减轻了VC[44]。这些结果表明，CKD中sKL和mKL都是VC的潜在治疗靶点。

FGF-23与VC进展的关联仍有争议。在一项研究[45]中，腺嘌呤饮食诱导的CKD模型小鼠的FGF-23升高，研究者发现升高的FGF-23通过将血清磷酸盐维持在正常范围内，在CKD期间具有保护作用；肾病发作期间抑制FGF-23会导致血清磷升高、更严重的肾脏疾病和心脏肥大。这表明FGF-23升高可能是CKD中适应KL下降的结果，其本身不会增加磷酸盐诱导的钙化。值得注意的是，无论KL下降还是FGF-23升高，最终均会导致高磷血症(VC相关性最强的诱导因素)[46]。CKD中过饱和的磷酸盐会形成磷酸钙沉淀，继而被血清蛋白胎球蛋白A吸附，形成钙蛋白颗粒，从而诱导血管平滑肌细胞钙化及巨噬细胞先天免疫反应[47]。因此，血管平滑肌细胞向分泌表型的转化在VC中起关键作用。此外，sKL升高或FGF-23降低还可能与2型糖尿病(type 2 diabetes mellitus，T2DM)患者动脉粥样硬化发展有关[48]。KL可以通过FGFR1和细胞外调节蛋白激酶1/2(extracellular signal-regulated kinase 1/2，ERK1/2)通路减少细胞凋亡和衰老，改变磷酸盐诱导的VC，影响动脉粥样硬化的发生和发展[49]。

CKD中过度活跃的RAAS通过多种机制促进肾损伤，加速疾病进展并增加病死率。血管紧张素II(angiotensin II，Ang II)除了引起高血压，还可以诱导TGF-β表达、促进ROS产生并增加肾脏炎症[50]。Pi等[51]报道了FGF-23升高与RAAS激活的关系，Ang II治疗增加了骨组织中FGF-23的表达，并诱导血压升高和左心室肥厚；而FGF-23可以抑制肾脏血管紧张素转化酶2活性，从而促进Ang II的促高血压作用。这些结果表明，FGF-23可能参与CKD中调节血流动力学的全身和旁分泌网络，CKD中的高血压可能与KL下降导致的FGF-23升高有关，并与RAAS系统相互串扰，相反，外源性递送KL抑制了RAAS系统，并使血压正常化[52]。

4. KL作为生物标志物的应用前景

4.1. 血清sKL可能作为诊断标志物

已有的研究[53]结果表明：sKL可在尿液、唾液、血液或脑脊液等体液中被检测到。同样的，临床上可以通过测量血液中的KL水平来预测某些疾病的风险，如血浆sKL的降低被认为是T2DM患者DN进展的指标[54]。慢性腹膜透析患儿血清sKL水平显著低于健康对照组[55]；在FGF-23增加之前，sKL显著降低，这在暴露于高磷饮食的CKD小鼠中更为明显[56]，并且随着CKD分期的加重，sKL水平逐渐降低[57]。sKL的降低可能反映了患者的估计肾小球滤过率(estimated glomerular filtration rate，eGFR)下降，在CKD 1~5期患者肾活检中，经调整年龄和其他矿物质参数后，KL mRNA的表达水平与eGFR呈正相关[58]。此外，在CKD中，血清sKL在血肌酐(serum creatinine，SCr)和FGF-23升高之前已呈现线性下降趋势，并与疾病进展相关[5]。因此，血清sKL被认为可能是早期肾损伤的生物标志物，其检测可为早期诊断提供依据[59]。

4.2. 尿液sKL可能不足以作为诊断标志物

目前尚无研究将尿液sKL作为肾脏KL的指标，仅提出以血清的sKL为指标[36]，可能是由于尚不清楚sKL经肾脏清除的潜在机制。目前为止，已经提出了尿液中存在sKL的可能机制：sKL由肾小管转胞吞作用和肾小管蛋白酶脱落，因此，CKD中肾功能损害可能也会降低血sKL清除率[60]。此外，对于尿液中sKL的测定，其在新鲜排空尿液中的浓度明显高于储存样本中的浓度，这意味着sKL在储存的人类尿液中是不稳定的[61]。尿sKL在CKD的早期阶段开始增加而不是减少，这可能有利于解释早期CKD患者血清中观察到的sKL减少。可以肯定的是，CKD小鼠血清和尿液中sKL的下降遵循相同的趋势，且血液sKL显示出更明显的下降[56]。

4.3. sKL与CKD预后的关联

多项研究探讨了sKL与CKD进展及预后的关系，但结论尚不一致。例如，早期的2项横断面研究提示sKL与CKD进展呈负相关[62-63]，而一项近期的前瞻性队列研究[64]在校正包括FGF-23在内的多项因素后，未发现sKL与CKD进展风险显著相关，但FGF-23仍与死亡及住院风险独立相关，提示sKL在预测疾病进展方面的价值可能有限。关于sKL与CKD预后的关系，现有证据呈现不一致的模式。一项荟萃分析[65]显示sKL水平与全因死亡、心血管死亡及终末期肾病风险呈线性负相关。然而，另2项研究[66-67]则报告sKL与全因死亡率之间存在“L”形关联，即仅在较低水平范围内sKL下降与死亡风险上升相关。这种差异可能与研究人群异质性、sKL检测方法(如抗体与平台不同)有关，也可能反映sKL与CKD预后之间存在阈值效应或受其他因素调节。此外，多项研究[68-69]提示联合指标可能更具临床意义。低sKL/FGF-23比值与肾脏事件风险增加相关[68]，且在血液透析患者中，sKL降低预示更多不良结局[69]。这些结果表明sKL与FGF-23等指标联合评估可能比单一指标更能反映病理生理状态与预后。综上，sKL作为CKD预后标志物的价值仍存在争议，其与临床结局的关系可能非线性，且易受检测方法影响。未来需统一检测标准，并深入探讨sKL与其他指标在CKD进展中的协同作用机制(表1)。

表1.

近5年关于sKL与CKD进程及预后关系的临床研究

Table 1 Clinical studies on the relationship between sKL and CKD progression and prognosis in the past 5 years

研究类型 研究对象 sKL测量方法 主要发现 文献
横断面研究 13 589名40~79岁参与者(含2 733名CKD患者)

血清IBL

ELISA

sKL<6.85时与CKD≥1期和白蛋白尿的发生呈负相关

(OR=0.44，P<0.001)

 [62]
横断面研究 2 989名T2DM患者 血清IBL夹心ELISA

sKL较高者更年轻、女性更多、CKD患病率较低；

eGFR与sKL呈正相关(β=2.21，P<0.001)

 [63]
前瞻性观察研究 1 088名慢性肾功能不全患者 — 高、低sKL组的生存率及CKD进展无显著差异 [64]
荟萃分析 成年CKD或ESKD患者 — 低sKL与全因死亡率(OR=1.97)、CKD进展(OR=2.48)、ESKD或肾脏替代疗法风险增加(OR=2.30)显著相关(均P<0.01) [65]
前瞻性队列研究 2 456名CKD患者

血清IBL

ELISA

sKL每增加100 pg/mL，全因死亡风险降低4%(HR=0.96)；sKL<760 pg/mL时，sKL与全因死亡率呈显著负相关

(HR=0.86，P<0.05)

 [66]
横断面研究 2 418名40~79岁1~4期CKD患者

血清IBL

ELISA

sKL<700 pg/mL时全因死亡(HR=1.52)及心血管死亡

(HR=1.58)风险显著增加(均P<0.01)

 [67]
多中心前瞻性队列研究 2 099名CKD 1~5期透析前研究参与者

血清IBL

ELISA

低sKL/FGF-23比与肾脏事件风险升高有关(HR=1.36，

P=0.01)，与CV事件/死亡结局无关(P=0.153)

 [68]
荟萃分析 992名维持血液透析>3个月的CKD患者 — 低sKL水平与心血管事件(HR=1.73)和全因死亡率(HR=2.34)增加相关(均P=0.05) [69]
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sKL：可溶型克老素；CKD：慢性肾脏病；OR：比值比；HR：风险比；CI：置信区间；ELISA：酶联免疫吸附试验；GFR：肾小球滤过率；eGFR：估计肾小球滤过率；ESKD：终末期肾病；CV：心血管；BMI：身体质量指数；HbA1c：糖化血红蛋白。

4.4. 检测技术的提升有助于推动KL的临床应用

目前，sKL检测的标准化尚未实现[70]。现有的酶联免疫吸附试验(enzyme-linked immunosorbent assay，ELISA)检测方法大多还无法区分sKL和seKL，更加不能区分血清中的KL是由mKL细胞外结构域的脱落还是其转录本的选择性剪接引起的。然而，由于mRNA选择性剪接产生的seKL在C端包含一段独特的15个AA序列。因此，目前开发了一种特异性检测这种seKL亚型的方法，可能为研究不同形式KL对疾病的影响提供新的工具[10, 71]。此外，还有一种测量方法为免疫沉淀-蛋白质印迹，与ELISA相比，它与eGFR的相关性更好，捕获效果更好，并且不易受到蛋白酶抑制剂的影响，但其更复杂，难以用于临床常规检测[70]。已有研究[72]对FGF-23的C端结合肽进行改造，使其与KL结合力提升了2 300倍，为构建更加灵敏的检测方法提供了基础。考虑到CKD患者血清中sKL水平较低，提高KL检测的精确度和灵敏度将极大地促进KL作为疾病标志物的研究和临床应用。

5. 临床药物开发途径和开发现状

KL的表达随着年龄的增长和疾病进展而下降，并可能直接参与疾病发生、发展。临床前研究[27, 73]表明：补充外源性sKL可以减轻肾纤维化、EMT，是一种安全有效的治疗肾损伤和保护肾功能的方法。KL作为一种胞外蛋白和膜蛋白，其体内水平取决于其生成和降解的平衡。因此，靶向KL治疗药物的开发主要从3个方面展开：1)通过上游机制增加KL的表达；2)通过下游机制减少KL的降解；3)通过外源性递送替代提高其水平(表2)。未来可以通过KL基因疗法、KL蛋白注射或抑制KL蛋白降解，以延缓疾病的进展。

表2.

提高KL表达的已知机制和调节物质

Table 2 Known mechanisms and substances for increasing KL levels

来源 作用机制或分类 已知物质或药物 潜在缺点及不良反应 文献
外源性递送 KL基因递送 AAV质粒、PPSK纳米颗粒 目前仅限于动物，安全性未知 [74-75]
多肽、蛋白递送 多肽、KL重组蛋白 易降解、需多次注射、引发免疫反应 [76]
内源性上游机制 抑制ADAM

染料木黄酮、莱茵、氮杂胞苷、

5-氮杂-2’-脱氧胞苷、姜黄、帕立骨化醇、

双氢青蒿、化合物H

 易引发癌症、自身免疫性疾病、代谢性与心血管疾病等 [30, 77-83]
抑制组蛋白脱乙酰酶 曲古霉素A、丙戊酸 易引起代谢疾病、免疫失调、器官损伤 [84]
调节转录因子(PPARγ、Pax4、NF-κB等) 噻唑烷二酮类、曲古抑菌素A、Pax4、黄芪甲苷IV、吡咯烷二硫代氨基甲酸酯、异土木香内酯、荷叶碱、白藜芦醇 易诱发肿瘤 [83, 85-90]

抑制相应

RNA功能

miRNA-152、miRNA-30a、LncRNA-

SNHG29

 易降解、干扰非目标基因的表达、免疫失调、癌症 [91-92]
其他 人参、人参皂苷、5-氨基咪唑-4-羧酰胺核糖核苷、双胍类、螺内酯、维生素D、氯沙坦、雷帕霉、他汀类 — [93-100]
内源性下游机制 调节ADAM 藁本内酯、胰岛素 脱靶效应、代谢和心血管影响 [9, 101]
抑制ER应力、ERAD 4-PBA、牛磺熊去氧胆酸、(+)-硫辛酸、亚瑞司他丁I 破坏细胞稳态、代谢紊乱

[32, 36,

102-103]
去泛素化 — —
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AAV：腺相关病毒；PPSK：聚多巴胺-聚乙烯亚胺-L-丝氨酸-克老素；Pax4：配对盒基因4；miRNA：微小RNA；LncRNA：长链非编码RNA；ADAM：DNA甲基转移酶；ER：内质网；ERAD：内质网相关蛋白降解；4-PBA：4-苯基丁酸；PPARγ：过氧化物酶体增殖物激活受体γ；NF-κB：核因子κB。

5.1. 外源性KL提升途径

作为具有抗衰老和疾病保护作用的重要蛋白，KL的基因治疗具有能够长期表达、只需一次给药的优势。研究[74]表明：递送编码分泌sKL的腺相关病毒血清型9有效地增加了血清中sKL的浓度，从而使小鼠寿命延长20%并改善了骨组织老化的表型和神经系统的认知能力。纳米颗粒技术的突破解决了传统病毒载体的局限性：刘庆华团队[75]发现负载KL质粒的纳米颗粒能够特异靶向损伤的肾小管细胞，通过影响过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor，PPAR)相关信号通路阻止AKI向CKD的进展。这一研究克服了之前KL基因治疗严重依赖病毒载体、可能触发免疫反应和潜在遗传毒性的限制，表现出良好的生物相容性。

对KL进行多肽药物的开发同样重要。已有多家公司对KL重组蛋白及其与FGF-23的融合多肽应用申请专利。如前所述，外源性sKL递送被证明能够抑制肾纤维化、EMT和VC。然而，由于其体积大、结构复杂和生产成本高，它在临床上的实用性受到阻碍。刘友华团队[76]将人源性KL的KL1结构域截短成30个AA的短肽并进行筛选，发现KL 57~86 AA (KP1)靶向TGF-β，抑制肾脏纤维化；KP4能够抑制FGF2信号通路，抑制纤维化；KL 186~215 AA (KP6)缓解DN的蛋白尿，减轻肾小球肥大，减轻足细胞损伤，改善肾小球硬化和间质纤维化病变，但不影响血清磷和钙水平[104]，用AAV递送KL的功能性片段KP1+KP4+KP6 (mini-KL)，能缓解UUO小鼠的纤维化。注射重组蛋白和多肽具有起效快、作用直接等优点，但其半衰期短，需多次注射，且在人体可能引起潜在的免疫反应，一定程度上限制了其临床应用(表2)。

5.2. 内源性KL提升途径

目前对内源性KL的调控主要集中在激活KL的转录。这类药物通过分子机制恢复CKD中被下调的内源性KL，而非依靠外源性补充。小分子药物的开发主要针对KL启动子：研究者[105]通过构建KL启动子驱动的荧光素酶报告系统，对15万个小分子化合物进行筛选，已发现化合物G、H、I能够增加KL的表达并增强FGF-23的信号转导。后续发现的化合物21、25不仅能够增加KL的表达，还可缓解阿尔茨海默病[106]。此外，其他多种天然小分子或药物也具有刺激KL表达的作用(表2)。

5.3. 针对泛素化抑制的内源性KL调控新靶点

UPS作为降解胞内蛋白的重要机制，通过E1泛素激活酶、E2泛素偶联酶和E3泛素连接酶的级联反应实现靶蛋白的特异性降解[107]。研究[32, 36]发现：ERAD的特异性抑制恢复了KL水平，但未恢复其mRNA水平。另一项研究[70]则发现：即使在存在外源性sKL的情况下，CKD患者的sKL水平在用蛋白酶抑制剂治疗后也没有显著恢复，这提示sKL有通过非蛋白酶体途径降解的可能性。

蛋白水解靶向嵌合体(proteolysis-targeting chimera，PROTAC)和DUBTAC作为UPS的衍生技术，近年来备受关注。PROTAC是一种利用UPS降解靶蛋白的药物开发技术。近年来，其快速发展为药物研发提供了新的策略，相关药物已经大量进入临床研究[108]。大多数针对单个蛋白质的调控通过与靶蛋白相互作用，从而进行特异性活性调节，而PROTAC则针对通常难以靶向的蛋白质开发[109]。PROTAC是一种诱导邻近方法，采用异双功能分子[由目标蛋白质(protein of interest，POI)配体与E3连接酶募集体通过中间体连接而成]，诱导蛋白质底物、PROTAC和E3连接酶三元复合物的形成[110]，从而靶向降解胞内、膜表面或细胞外的任何潜在蛋白质靶标(图2)。而且，PROTAC只需要与靶蛋白瞬时结合即可催化诱导泛素化和降解。

图2.

图2

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PROTAC和DUBTAC的作用机制

Figure 2 Mechanisms of PROTAC and DUBTAC

Ub: Ubiquitin; ATP: Adenosine triphosphate; AMP: Adenosine monophosphate; POI: Protein of interest; DUB: Deubiquitinating enzyme; Ub: Ubiquitin; PROTAC: Proteolysis-targeting chimera; DUBTAC: Deubiquitinase-targeting chimera.

相较于PROTAC清除致病蛋白的功能，DUBTAC则用于保护功能受损或不足的蛋白(图2)。蛋白质泛素化是一个可逆的过程，结合的泛素可以被去泛素化酶(deubiquitinating enzyme，DUB)去除[111]。DUBTAC同样是异双功能小分子，由DUB募集剂、POI配体和连接2个部分的中间体组成。DUBTAC可以通过将DUB拖到POI附近以触发POI的去泛素化，提高内源性KL蛋白的水平(图2)。KL在尿液和血液中不稳定[61]，且缺乏特异性酶活性位点。DUBTAC技术有望为KL靶向药物的开发实现新的突破[112]。

近期研究[72]利用亲和选择质谱(affinity selection mass spectrometry，AS-MS)开发的KL选择性探针可能为DUBTAC的POI配体设计提供思路，与之前模拟FGF-23 C端区域设计的10肽相比，这些肽对KL的结合亲和力提高了约2 300倍。其次，需要确定一种靶向DUB上的变构位点而不抑制DUB功能的小分子募集子，以开发DUB募集子[112]。化学蛋白质组学技术，如基于活性的蛋白质分析(activity-based protein profiling，ABPP)，通过反应型化学探针和先进的基于定量质谱的蛋白质组学方法，将能够发现可以用小分子配体靶向的“可配体热点”[113]。

目前，DUBTAC已被用于靶向支气管囊性纤维化和肿瘤的研究[112]。尽管存在100多种人类DUB，但目前只有含有卵巢肿瘤结构域的泛素醛结合蛋白1(ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1，OTUB1)、泛素特异性蛋白酶(ubiquitin-specific protease，USP)7、USP1和USP28被开发，这项技术还处在早期阶段[114-117]。此外，KL的特异性DUB尚未明确，且其降解乃至泛素化机制仍不清晰。已有研究[118]在肺癌模型中探究了KL泛素化的影响，但是在CKD患者中，关于KL的泛素化和去泛素化的机制尚不清楚。研究[119]显示：E3泛素-蛋白连接酶滑液蛋白在纤维化肾脏中显著增加，表明其可能是ERAD途径中识别KL的特异性E3连接酶。此外，基于CRISPR-Cas9系统的基因组规模筛选技术有助于鉴别调控KL去泛素化的基因[120]。未来通过KL特异性DUB合成DUBTAC，将有助于合成减少CKD中KL降解的新药。

值得注意的是，在走向临床应用之前，DUBTAC技术可能面临着配体稀缺、递送效率低和人体安全性问题。此外，DUBTAC技术可能有着非特异性的一面：DUB不仅可以裂解蛋白质的泛素链以稳定蛋白质底物，还可以靶向某些底物上非蛋白质水解的泛素链，这可能影响蛋白质周转或抑制某些信号通路[121]。但总体而言，DUBTAC仍有望成为KL内源性水平调控的有前景的靶标。

6. 结语与展望

KL在肾脏中特异性高表达，在CKD和AKI中表达均显著降低，而且在CKD的早期就能检测到血清sKL下调，有望作为残存肾单位的检测指标。但在将其作为生物标志物前，还应在机制层面解释其水平变化：目前血清sKL水平下降仍不能完美解释所有CKD类型的所有阶段，如为何DN中的sKL反而上升[122]，是否与CKD病因及临床分期有关，CKD中究竟是血sKL还是肾小管的mKL更具有保护作用？终末期肾病的尿毒症条件可能使KL易于降解[70]，CKD的治疗药物如螺内酯[96]或活性维生素D[97]本身也会影响sKL水平，同时，CKD中其他器官代偿性分泌sKL也可能影响检测[7]。sKL的肾脏保护作用是否取决于血清总水平而与肾脏的分泌水平无关？此外，导致目前KL尚未被纳入临床常规检测的原因还包括：1)3种常用的ELISA试剂盒使用的KL抗体靶点，灵敏度差异大，可能导致测定的一致性较差[123]，导致不同CKD阶段和种类的sKL可比性低。2)尿液中sKL不稳定，且ELISA相比免疫沉淀-蛋白质印迹，对样本的蛋白酶添加和冻融次数似乎更敏感[70]。因此，研究者们需要探索CKD中导致sKL下降的复杂调控网络，统一检测方案和样本的处理方法，或者开发新的检测手段，才能最终推动KL作为生物标志物的进展。

研究[74-75]表明：外源性sKL的补充恢复了KL缺乏的表型，然而，外源性sKL不稳定，需要多次给药，基因疗法仅限于在动物体内研究，在人体可能面临未知的安全性问题。针对上游机制的药物，特别是调控基因的药物未在人体测试，可能具有生物安全性问题，而且不具有靶向性，并不总是导致KL水平增加[124]。抑制内源性KL降解可能在KL的临床治疗转化上更为关键。近年来的研究[125]发现：调控ER应激能抑制内源性KL降解，抑制KL的胞内降解能同时提高mKL和sKL水平，特别地，KL水平提高也能降低CKD中过高的ER应力，减轻肾损伤。基于DUBTAC技术的新药开发是KL泛素化靶标管理的理想途径，其应用可能解决KL的难以成药性问题，以及人工操纵ERAD可能带来的不良反应[126]。

未来，对KL蛋白在CKD中的应用研究有以下3个重点方向：1)进一步探明不同形式的KL(mKL、sKL、seKL)在不同组织中的表达和作用机制，以明确各自对于疾病预测的准确性。同时，开发更加灵敏和特异的检测方法。2)明确sKL和seKL如何介导细胞内的信号通路，是否有细胞表面受体，能否通过文库筛选、邻近标记技术或光交联技术来鉴定其受体。3)阐明CKD中KL降解的详细通路，明确KL蛋白的泛素化修饰和去泛素化修饰机制，为DUBTAC分子的构建提供理论基础。

KL在临床上已被验证与CKD的进展相关，其蛋白下调已经作为衰老、肾移植预后和CKD诊断指标应用于临床[53, 127-128]，但是其诊断和治疗仍未实现质的突破，作为常规的检测指标及临床应用还任重而道远，还需基础和临床研究人员进行配合，以推动其临床应用和发展，使KL成为CKD早期诊断、进展监测和治疗的重要靶点。

基金资助

广东医科大学附属医院高层次人才科研启动项目(GCC2023014)；广东医科大学本科生创新创业教育基地项目(JDXM2024001F)。This work was supported by the High-Level Talents Scientific Research Start-Up Funds of the Affiliated Hospital of Guangdong Medical University (GCC2023014) and the Guangdong Medical University Undergraduate Innovation and Entrepreneurship Education Base Project (JDXM2024001F), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

李奕烽 论文构思、撰写和修改；陈桂鸿、陈美钧、林燕、罗成、郭玲欣 文献收集和讨论；胡文宝 论文指导和修改；刘征兆 论文指导。所有作者阅读并同意最终的文本。

Footnotes

http://dx.chinadoi.cn/10.11817/j.issn.1672-7347.2025.250245

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2025101900.pdf

参考文献

  • 1. Lousa I, Reis F, Beirão I, et al. New potential biomarkers for chronic kidney disease management-a review of the literature[J]. Int J Mol Sci, 2020, 22(1): 43. 10.3390/ijms22010043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Guerra JMA, Martinez-Martinez JI. Multifactorial chronic kidney disease[J/OL]. Nephrol Dial Transplant, 2025: gfaf122[2025-05-10]. 10.1093/ndt/gfaf122. [DOI] [PubMed] [Google Scholar]
  • 3. 王雪, 史可香, 余灿清, 等. 中国10个地区成年人慢性肾脏病流行情况及其生活方式影响因素[J]. 中华流行病学杂志, 2023, 44(03)：386-392. 10.3760/cma.j.cn112338-20220801-00680. [DOI] [PubMed] [Google Scholar]; WANG Xiang, SHI Kexiang, YU Canqing, et al. Prevalence of chronic kidney disease and its association with lifestyle factors in adults from 10 regions of China[J]. Chinese Journal of Epidemiology, 2023, 44(3): 386-392. 10.3760/cma.j.cn112338-20220801-00680. [DOI] [PubMed] [Google Scholar]
  • 4. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing[J]. Nature, 1997, 390(6655): 45-51. 10.1038/36285. [DOI] [PubMed] [Google Scholar]
  • 5. Shimamura Y, Hamada K, Inoue K, et al. Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis[J]. Clin Exp Nephrol, 2012, 16(5): 722-729. 10.1007/s10157-012-0621-7. [DOI] [PubMed] [Google Scholar]
  • 6. Rotondi S, Pasquali M, Tartaglione L, et al. Solubleα-klotho serum levels in chronic kidney disease[J]. Int J Endocrinol, 2015, 2015: 872193. 10.1155/2015/872193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Lim K, Groen A, Molostvov G, et al. α-klotho expression in human tissues[J/OL]. J Clin Endocrinol Metab, 2015, 100(10): E1308-E1318[2025-05-10]. 10.1210/jc.2015-1800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Liu JH, Wang HC, Liu QY, et al. Klotho exerts protection in chronic kidney disease associated with regulating inflammatory response and lipid metabolism[J]. Cell Biosci, 2024, 14(1): 46. 10.1186/s13578-024-01226-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Chen CD, Podvin S, Gillespie E, et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17[J]. Proc Natl Acad Sci USA, 2007, 104(50): 19796-19801. 10.1073/pnas.0709805104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Jadhav S, Tripathi S, Chandrekar A, et al. A novel antibody for the detection of alternatively spliced secreted KLOTHO isoform in human plasma[J/OL]. PLoS One, 2021, 16(1): e0245614[2025-05-10]. 10.1371/journal.pone.0245614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain[J]. Biochem Biophys Res Commun, 2000, 277(2): 494-498. 10.1006/bbrc.2000.3696. [DOI] [PubMed] [Google Scholar]
  • 12. Kuro-o M. Phosphate and klotho[J/OL]. Kidney Int, 2011, 79: S20-S23[2025-05-10]. 10.1038/ki.2011.26. [DOI] [PubMed] [Google Scholar]
  • 13. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23[J]. Nature, 2006, 444(7120): 770-774. 10.1038/nature05315. [DOI] [PubMed] [Google Scholar]
  • 14. Chen GZ, Liu Y, Goetz R, et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling[J]. Nature, 2018, 553(7689): 461-466. 10.1038/nature25451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Chen LF, Fu LL, Sun JC, et al. Structural basis for FGF hormone signalling[J]. Nature, 2023, 618(7966): 862-870. 10.1038/s41586-023-06155-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Erben RG. Physiological actions of fibroblast growth factor-23[J]. Front Endocrinol (Lausanne), 2018, 9: 267. 10.3389/fendo.2018.00267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Andrukhova O, Smorodchenko A, Egerbacher M, et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel[J]. EMBO J, 2014, 33(3): 229-246. 10.1002/embj.201284188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Typiak M, Piwkowska A. Antiinflammatory actions of klotho: implications for therapy of diabetic nephropathy[J]. Int J Mol Sci, 2021, 22(2): 956. 10.3390/ijms22020956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Xiang T, Luo XD, Ye L, et al. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway[J]. Epilepsy Behav, 2022, 128: 108509. 10.1016/j.yebeh.2021.108509. [DOI] [PubMed] [Google Scholar]
  • 20. Xia K, Qiu T, Jian YH, et al. Degradation of histone deacetylase 6 alleviates ROS-mediated apoptosis in renal ischemia-reperfusion injury[J]. Biomed Pharmacother, 2023, 165: 115128. 10.1016/j.biopha.2023.115128. [DOI] [PubMed] [Google Scholar]
  • 21. Yoshikawa R, Yamamoto H, Nakahashi O, et al. The age-related changes of dietary phosphate responsiveness in plasma 1, 25-dihydroxyvitamin D levels and renal Cyp27b1 and Cyp24a1 gene expression is associated with renal α-Klotho gene expression in mice[J]. J Clin Biochem Nutr, 2018, 62(1): 68-74. 10.3164/jcbn.17-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Takeshita A, Kawakami K, Furushima K, et al. Central role of the proximal tubular αKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism[J]. Sci Rep, 2018, 8(1): 6917. 10.1038/s41598-018-25087-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. 梁婧, 张宗敏, 周满红. 肾脏衰老相关分子机制的研究进展[J]. 中国老年学杂志, 2024, 44(7): 1778-1781. 10.3969/j.issn.1005-9202.2024.07.057. [DOI] [Google Scholar]; LIANG Jing, ZHANG Zongmin, ZHOU Manhong. Research progress on molecular mechanism related to renal aging[J]. Chinese Journal of Gerontology, 2024, 44(7): 1778-1781. 10.3969/j.issn.1005-9202.2024.07.057. [DOI] [Google Scholar]
  • 24. Lim SW, Shin YJ, Luo K, et al. Effect of Klotho on autophagy clearance in tacrolimus-induced renal injury[J]. FASEB J, 2019, 33(2): 2694-2706. 10.1096/fj.201800751R. [DOI] [PubMed] [Google Scholar]
  • 25. Xue M, Yang F, Le Y, et al. Klotho protects against diabetic kidney disease via AMPK- and ERK-mediated autophagy[J]. Acta Diabetol, 2021, 58(10): 1413-1423. 10.1007/s00592-021-01736-4. [DOI] [PubMed] [Google Scholar]
  • 26. Guan X, Nie L, He T, et al. Klotho suppresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling[J]. J Pathol, 2014, 234(4): 560-572. 10.1002/path.4420. [DOI] [PubMed] [Google Scholar]
  • 27. Zhou LL, Li YJ, Zhou D, et al. Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling[J]. J Am Soc Nephrol, 2013, 24(5): 771-785. 10.1681/ASN.2012080865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Ma ZX, Liu JJ, Li J, et al. Klotho levels are decreased and associated with enhanced oxidative stress and inflammation in the aqueous humor in patients with exudative age-related macular degeneration[J]. Ocul Immunol Inflamm, 2022, 30(3): 630-637. 10.1080/09273948.2020.1828488. [DOI] [PubMed] [Google Scholar]
  • 29. de Seigneux S, Martin PY. Phosphate and FGF23 in the renoprotective benefit of RAAS inhibition[J]. Pharmacol Res, 2016, 106: 87-91. 10.1016/j.phrs.2016.02.015. [DOI] [PubMed] [Google Scholar]
  • 30. Azuma M, Koyama D, Kikuchi J, et al. Promoter methylation confers kidney-specific expression of the Klotho gene[J]. FASEB J, 2012, 26(10): 4264-4274. 10.1096/fj.12-211631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Liu QF, Li SS, Yu LX, et al. CCL5 suppresses klotho expression via p-STAT3/DNA Methyltransferase1-mediated promoter hypermethylation[J]. Front Physiol, 2022, 13: 856088. 10.3389/fphys.2022.856088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Delitsikou V, Jarad G, Rajaram RD, et al. Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress[J]. FASEB J, 2020, 34(2): 2087-2104. 10.1096/fj.201900893R. [DOI] [PubMed] [Google Scholar]
  • 33. Yu N, Yang L, Ling LL, et al. Curcumin attenuates angiotensin II-induced podocyte injury and apoptosis by inhibiting endoplasmic reticulum stress[J]. FEBS Open Bio, 2020, 10(10): 1957-1966. 10.1002/2211-5463.12946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Mohammed-Ali Z, Lu C, Marway MK, et al. Endoplasmic reticulum stress inhibition attenuates hypertensive chronic kidney disease through reduction in proteinuria[J]. Sci Rep, 2017, 7: 41572. 10.1038/srep41572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Bhattacharya A, Wei JC, Song WX, et al. SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer[J]. iScience, 2022, 25(10): 105183. 10.1016/j.isci.2022.105183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Li SS, Kong JW, Yu LX, et al. Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice[J]. Int J Med Sci, 2022, 19(2): 321-330. 10.7150/ijms.68137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Takashi Y, Fukumoto S. Phosphate-sensing and regulatory mechanism of FGF23 production[J]. J Endocrinol Invest, 2020, 43(7): 877-883. 10.1007/s40618-020-01205-9. [DOI] [PubMed] [Google Scholar]
  • 38. The E, Zhai YF, Yao QZ, et al. Molecular interaction of soluble klotho with FGF23 in the pathobiology of aortic valve lesions induced by chronic kidney disease[J]. Int J Biol Sci, 2024, 20(9): 3412-3425. 10.7150/ijbs.92447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Schumock GT, Andress DL, Marx SE, et al. Association of secondary hyperparathyroidism with CKD progression, health care costs and survival in diabetic predialysis CKD patients [J/OL]. Nephron Clin Pract, 2009, 113(1): c54-c61[2025-05-10]. 10.1159/000228076. [DOI] [PubMed] [Google Scholar]
  • 40. Desbiens LC, Sidibé A, Ung RV, et al. FGF23-klotho axis and fractures in patients without and with early CKD: a case-cohort analysis of CARTaGENE[J/OL]. J Clin Endocrinol Metab, 2022, 107(6): e2502-e2512[2025-05-10]. 10.1210/clinem/dgac071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Fang YF, Ginsberg C, Seifert M, et al. CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder[J]. J Am Soc Nephrol, 2014, 25(8): 1760-1773. 10.1681/ASN.2013080818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Nagy E, Sobh MM, Abdalbary M, et al. Is adynamic bone always a disease? lessons from patients with chronic kidney disease[J]. J Clin Med, 2022, 11(23): 7130. 10.3390/jcm11237130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Zhao Y, Zhao MM, Cai Y, et al. Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation[J]. Kidney Int, 2015, 88(4): 711-721. 10.1038/ki.2015.160. [DOI] [PubMed] [Google Scholar]
  • 44. Dai L, Qureshi AR, Witasp A, et al. Early vascular ageing and cellular senescence in chronic kidney disease[J]. Comput Struct Biotechnol J, 2019, 17: 721-729. 10.1016/j.csbj.2019.06.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Clinkenbeard EL, Noonan ML, Thomas JC, et al. Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD[J/OL]. JCI Insight, 2019, 4(4): e123817[2025-05-10]. 10.1172/jci.insight.123817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Liang XH, Li YK, Wang P, et al. Key regulators of vascular calcification in chronic kidney disease: Hyperphosphatemia, BMP2, and RUNX2[J/OL]. PeerJ, 2024, 12: e18063[2025-05-10]. 10.7717/peerj.18063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Kuro-O M. Klotho and calciprotein particles as therapeutic targets against accelerated ageing[J]. Clin Sci (Lond), 2021, 135(15): 1915-1927. 10.1042/CS20201453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Bi J, Zheng M, Li K, et al. Relationships of serum FGF23 and α-klotho with atherosclerosis in patients with type 2 diabetes mellitus[J]. Cardiovasc Diabetol, 2024, 23(1): 128. 10.1186/s12933-024-02205-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Jia Z, Liu Q, Xie Y, et al. Klotho/FGF23 axis regulates cardiomyocyte apoptosis and cytokine release through ERK/MAPK pathway[J]. Cardiovasc Toxicol, 2023, 23(9/10): 317-328. 10.1007/s12012-023-09805-6. [DOI] [PubMed] [Google Scholar]
  • 50. Siragy HM, Carey RM. Role of the intrarenal renin-angiotensin- aldosterone system in chronic kidney disease[J]. Am J Nephrol, 2010, 31(6): 541-550. 10.1159/000313363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Trivedi MV, Jadhav HR, Gaikwad AB. Novel therapeutic targets for cardiorenal syndrome[J]. Drug Discov Today, 2025, 30(1): 104285. 10.1016/j.drudis.2024.104285. [DOI] [PubMed] [Google Scholar]
  • 52. Zhou LL, Mo HY, Miao JH, et al. Klotho ameliorates kidney injury and fibrosis and normalizes blood pressure by targeting the renin-angiotensin system[J]. Am J Pathol, 2015, 185(12): 3211-3223. 10.1016/j.ajpath.2015.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic[J]. Nat Med, 2022, 28(8): 1556-1568. 10.1038/s41591-022-01923-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Kim SS, Song SH, Kim IJ, et al. Decreased plasma α-Klotho predict progression of nephropathy with type 2 diabetic patients[J]. J Diabetes Complications, 2016, 30(5): 887-892. 10.1016/j.jdiacomp.2016.03.006. [DOI] [PubMed] [Google Scholar]
  • 55. Cano FJ, Freundlich M, Ceballos ML, et al. Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis[J]. Clin Kidney J, 2014, 7(5): 457-463. 10.1093/ckj/sfu074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Martín-Vírgala J, Fernández-Villabrille S, Martín-Carro B, et al. Serum and urinary soluble α-klotho as markers of kidney and vascular impairment[J]. Nutrients, 2023, 15(6): 1470. 10.3390/nu15061470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Pavik I, Jaeger P, Ebner L, et al. Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study[J]. Nephrol Dial Transplant, 2013, 28(2): 352-359. 10.1093/ndt/gfs460. [DOI] [PubMed] [Google Scholar]
  • 58. Sakan H, Nakatani K, Asai O, et al. Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism[J/OL]. PLoS One, 2014, 9(1): e86301[2025-05-10]. 10.1371/journal.pone.0086301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Fernández-Fernández B, Valiño-Rivas L, Sánchez-Niño MD, et al. Albuminuria downregulation of the anti-aging factor klotho: the missing link potentially explaining the association of pathological albuminuria with premature death[J]. Adv Ther, 2020, 37(Suppl 2): 62-72. 10.1007/s12325-019-01180-5. [DOI] [PubMed] [Google Scholar]
  • 60. Hu MC, Shi MJ, Zhang JN, et al. Renal production, uptake, and handling of circulating αKlotho[J]. J Am Soc Nephrol, 2016, 27(1): 79-90. 10.1681/ASN.2014101030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Adema AY, Vervloet MG, Blankenstein MA, et al. α-Klotho is unstable in human urine[J]. Kidney Int, 2015, 88(6): 1442-1444. 10.1038/ki.2015.238. [DOI] [PubMed] [Google Scholar]
  • 62. Zhang ZL, Zhou XH, Deng LH, et al. The association between serum soluble Klotho and chronic kidney disease among us adults ages 40 to 79 years: Cross-sectional study[J]. Front Public Health, 2022, 10: 995314. 10.3389/fpubh.2022.995314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Ciardullo S, Perseghin G. Soluble α-Klotho levels, glycemic control and renal function in US adults with type 2 diabetes[J]. Acta Diabetol, 2022, 59(6): 803-809. 10.1007/s00592-022-01865-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Edmonston D, Fuchs MAA, Burke EJ, et al. Klotho and clinical outcomes in CKD: findings from the chronic renal insufficiency cohort (CRIC) study[J/OL]. Am J Kidney Dis, 2024, 84(3): 349-360. e1[2025-05-10]. 10.1053/j.ajkd.2024.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Kanbay M, Brinza C, Ozbek L, et al. The association between klotho and kidney and cardiovascular outcomes: a comprehensive systematic review and meta-analysis[J/OL]. Clin Kidney J, 2024, 17(9): sfae255[2025-05-10]. 10.1093/ckj/sfae255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Han SS, Zhang XL, Wang XJ, et al. Association between serum klotho and all-cause mortality in chronic kidney disease: evidence from a prospective cohort study[J]. Am J Nephrol, 2024, 55(3): 273-283. 10.1159/000535808. [DOI] [PubMed] [Google Scholar]
  • 67. Liu LL, Jia JY, Cheng X, et al. The optimal cut-off values of Klotho for predicting all-cause and cardiovascular mortality among chronic kidney disease: results from NHANES[J]. Sci Rep, 2024, 14(1): 4647. 10.1038/s41598-024-52701-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Kim HJ, Kim Y, Kang M, et al. Low klotho/fibroblast growth factor 23 ratio is an independent risk factor for renal progression in chronic kidney disease: finding from KNOW-CKD[J]. Front Med (Lausanne), 2022, 9: 904963. 10.3389/fmed.2022.904963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Liu QF, Li SS, Yu LX, et al. The prognostic value of soluble Klotho in patients with haemodialysis: a systematic review and meta-analysis[J]. Ther Adv Chronic Dis, 2020, 11: 2040622320940176. 10.1177/2040622320940176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Neyra JA, Moe OW, Pastor J, et al. Performance of soluble Klotho assays in clinical samples of kidney disease[J]. Clin Kidney J, 2019, 13(2): 235-244. 10.1093/ckj/sfz085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Massó A, Sánchez A, Gimenez-Llort L, et al. Secreted and transmembrane αKlotho isoforms have different spatio-temporal profiles in the brain during aging and Alzheimer’s disease progression[J/OL]. PLoS One, 2015, 10(11): e0143623[2025-05-10]. 10.1371/journal.pone.0143623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Zhang PY, Ye XY, Wang JCK, et al. Development of an α- klotho recognizing high-affinity peptide probe from in-solution enrichment[J]. JACS Au, 2024, 4(4): 1334-1344. 10.1021/jacsau.3c00650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Takenaka T, Inoue T, Miyazaki T, et al. Klotho suppresses the renin-angiotensin system in adriamycin nephropathy[J]. Nephrol Dial Transplant, 2017, 32(5): 791-800. 10.1093/ndt/gfw340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Roig-Soriano J, Edo Á, Verdés S, et al. Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience[J]. Mol Ther, 2025, 33(4): 1449-1465. 10.1016/j.ymthe.2025.02.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Li HY, Ouyang YY, Lv HR, et al. Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells[J]. Biomaterials, 2025, 315: 122926. 10.1016/j.biomaterials.2024.122926. [DOI] [PubMed] [Google Scholar]
  • 76. Zhang XY, Li L, Tan HS, et al. Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation[J]. Theranostics, 2024, 14(1): 420-435. 10.7150/thno.89105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Li YN, Chen F, Wei A, et al. Klotho recovery by genistein via promoter histone acetylation and DNA demethylation mitigates renal fibrosis in mice[J]. J Mol Med (Berl), 2019, 97(4): 541-552. 10.1007/s00109-019-01759-z. [DOI] [PubMed] [Google Scholar]
  • 78. Zhang Q, Yin SS, Liu L, et al. Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal fibrosis in mice[J]. Sci Rep, 2016, 6: 34597. 10.1038/srep34597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79. Chen J, Zhang XY, Zhang H, et al. Indoxyl sulfate enhance the hypermethylation of klotho and promote the process of vascular calcification in chronic kidney disease[J]. Int J Biol Sci, 2016, 12(10): 1236-1246. 10.7150/ijbs.15195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Hu Y, Mou LJ, Yang FY, et al. Curcumin attenuates cyclosporine A-induced renal fibrosis by inhibiting hypermethylation of the klotho promoter[J]. Mol Med Rep, 2016, 14(4): 3229-3236. 10.3892/mmr.2016.5601. [DOI] [PubMed] [Google Scholar]
  • 81. Donate-Correa J, Henríquez-Palop F, Martín-Núñez E, et al. Effect of paricalcitol on FGF-23 and klotho in kidney transplant recipients[J]. Transplantation, 2016, 100(11): 2432-2438. 10.1097/TP.0000000000001339. [DOI] [PubMed] [Google Scholar]
  • 82. Zhou W, Chen MM, Liu HL, et al. Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho[J]. Acta Pharmacol Sin, 2022, 43(10): 2609-2623. 10.1038/s41401-022-00898-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Jung D, Xu YC, Sun ZJ. Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands[J]. Oncotarget, 2017, 8(29): 46745-46755. 10.18632/oncotarget.18608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Moreno JA, Izquierdo MC, Sanchez-Niño MD, et al. The inflammatory cytokines TWEAK and TNF-α reduce renal klotho expression through NF-κB[J]. J Am Soc Nephrol, 2011, 22(7): 1315-1325. 10.1681/ASN.2010101073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85. Zhang H, Li YY, Fan YB, et al. Klotho is a target gene of PPAR-gamma[J]. Kidney Int, 2008, 74(6): 732-739. 10.1038/ki.2008.244. [DOI] [PubMed] [Google Scholar]
  • 86. Lin WJ, Zhang Q, Liu L, et al. Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease[J]. Kidney Int, 2017, 92(3): 669-679. 10.1016/j.kint.2017.02.023. [DOI] [PubMed] [Google Scholar]
  • 87. He JX, Cui JL, Shi YM, et al. Astragaloside IV attenuates high-glucose-induced impairment in diabetic nephropathy by increasing klotho expression via the NF-κB/NLRP3 axis[J]. J Diabetes Res, 2023, 2023: 7423661. 10.1155/2023/7423661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Shimizu H, Bolati D, Adijiang A, et al. Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-ĸB[J]. Am J Nephrol, 2011, 33(4): 319-324. 10.1159/000324885. [DOI] [PubMed] [Google Scholar]
  • 89. Li HH, Chen WH, Chen YS, et al. Neferine attenuates acute kidney injury by inhibiting NF-κB signaling and upregulating klotho expression[J]. Front Pharmacol, 2019, 10: 1197. 10.3389/fphar.2019.01197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Hsu SC, Huang SM, Chen A, et al. Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway[J]. Int J Biochem Cell Biol, 2014, 53: 361-371. 10.1016/j.biocel.2014.06.002. [DOI] [PubMed] [Google Scholar]
  • 91. Yin SS, Zhang Q, Yang J, et al. TGFβ-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis[J]. Biochim Biophys Acta Mol Cell Res, 2017, 1864(7): 1207-1216. 10.1016/j.bbamcr.2017.03.002. [DOI] [PubMed] [Google Scholar]
  • 92. Huang C, Zhan JF, Chen YX, et al. LncRNA-SNHG29 inhibits vascular smooth muscle cell calcification by downregulating miR-200b-3p to activate the α-Klotho/FGFR1/FGF23 axis[J]. Cytokine, 2020, 136: 155243. 10.1016/j.cyto.2020.155243. [DOI] [PubMed] [Google Scholar]
  • 93. Lim SW, Shin YJ, Luo K, et al. Ginseng increases Klotho expression by FoxO3 - mediated manganese superoxide dismutase in a mouse model of tacrolimus-induced renal injury[J]. Aging (Albany NY), 2019, 11(15): 5548-5569. 10.18632/aging.102137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Li SS, He AL, Deng ZY, et al. Ginsenoside-Rg1 protects against renal fibrosis by regulating the Klotho/TGF-β1/smad signaling pathway in rats with obstructive nephropathy[J]. Biol Pharm Bull, 2018, 41(4): 585-591. 10.1248/bpb.b17-00934. [DOI] [PubMed] [Google Scholar]
  • 95. Vogt J, Wolf L, Hoelzle LE, et al. AMP-dependent kinase stimulates the expression of αKlotho[J]. FEBS Open Bio, 2024, 14(10): 1691-1700. 10.1002/2211-5463.13872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Alesutan I, Feger M, Pakladok T, et al. 25-Hydroxyvitamin D3 1-α-hydroxylase-dependent stimulation of renal klotho expression by spironolactone[J]. Kidney Blood Press Res, 2013, 37(4/5): 475-487. 10.1159/000355728. [DOI] [PubMed] [Google Scholar]
  • 97. Chen H, Zhang YJ, Miao YF, et al. Vitamin D inhibits ferroptosis and mitigates the kidney injury of prediabetic mice by activating the Klotho/p53 signaling pathway[J]. Apoptosis, 2024, 29(9/10): 1780-1792. 10.1007/s10495-024-01955-4. [DOI] [PubMed] [Google Scholar]
  • 98. Yoon HE, Ghee JY, Piao SG, et al. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy[J]. Nephrol Dial Transplant, 2011, 26(3): 800-813. 10.1093/ndt/gfq537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Tataranni T, Biondi G, Cariello M, et al. Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression[J]. Am J Transplant, 2011, 11(8): 1656-1664. 10.1111/j.1600-6143.2011.03590.x. [DOI] [PubMed] [Google Scholar]
  • 100. Mylonas KS, Peroulis M, Kapetanakis EI, et al. Myocardial expression of pluripotency, longevity, and proinflammatory genes in the context of hypercholesterolemia and statin treatment[J]. J Clin Med, 2024, 13(7): 1994. 10.3390/jcm13071994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. Kuang X, Zhou HJ, Thorne AH, et al. Neuroprotective effect of ligustilide through induction of α-secretase processing of both APP and klotho in a mouse model of Alzheimer’s disease[J]. Front Aging Neurosci, 2017, 9: 353. 10.3389/fnagi.2017.00353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Kale A, Shelke V, Habshi T, et al. ER stress modulated Klotho restoration: a prophylactic therapeutic strategy against acute kidney injury-diabetes comorbidity[J]. Biochim Biophys Acta Mol Basis Dis, 2024, 1870(1): 166905. 10.1016/j.bbadis.2023.166905. [DOI] [PubMed] [Google Scholar]
  • 103. Longhitano L, Distefano A, Musso N, et al. (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease[J]. J Transl Med, 2024, 22(1): 82. 10.1186/s12967-024-04880-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Chen XW, Tan HS, Xu J, et al. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/β-catenin signaling[J]. Kidney Int, 2022, 102(3): 506-520. 10.1016/j.kint.2022.04.028. [DOI] [PubMed] [Google Scholar]
  • 105. King GD, Chen CD, Huang MM, et al. Identification of novel small molecules that elevate Klotho expression[J]. Biochem J, 2012, 441(1): 453-461. 10.1042/BJ20101909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Abraham CR, Chen CD, Cuny GD, et al. Small-molecule Klotho enhancers as novel treatment of neurodegeneration[J]. Future Med Chem, 2012, 4(13): 1671-1679. 10.4155/fmc.12.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Kliza K, Husnjak K. Resolving the complexity of ubiquitin networks[J]. Front Mol Biosci, 2020, 7: 21. 10.3389/fmolb.2020.00021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue[J]. Nat Rev Drug Discov, 2022, 21(3): 181-200. 10.1038/s41573-021-00371-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109. Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins[J]. Nature, 2020, 584(7820): 291-297. 10.1038/s41586-020-2545-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110. Nalawansha DA, Crews CM. PROTACs: an emerging therapeutic modality in precision medicine[J]. Cell Chem Biol, 2020, 27(8): 998-1014. 10.1016/j.chembiol.2020.07.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111. Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation[J]. Annu Rev Biochem, 2017, 86: 159-192. 10.1146/annurev-biochem-061516-044916. [DOI] [PubMed] [Google Scholar]
  • 112. Henning NJ, Boike L, Spradlin JN, et al. Deubiquitinase-targeting chimeras for targeted protein stabilization[J]. Nat Chem Biol, 2022, 18(4): 412-421. 10.1038/s41589-022-00971-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113. Spradlin JN, Zhang E, Nomura DK. Reimagining druggability using chemoproteomic platforms[J]. Acc Chem Res, 2021, 54(7): 1801-1813. 10.1021/acs.accounts.1c00065. [DOI] [PubMed] [Google Scholar]
  • 114. Deng ZJ, Chen L, Qian C, et al. The first-In-class deubiquitinase-targeting Chimera stabilizes and activates cGAS[J/OL]. Angew Chem Int Ed, 2025, 64(3): e202415168[2025-05-10]. 10.1002/anie.202415168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115. Liu J, Hu XP, Luo KX, et al. USP7-based deubiquitinase-targeting chimeras stabilize AMPK[J/OL]. J Am Chem Soc, 2024: 10. 1021/jacs. 4c02373[2025-05-10]. 10.1021/jacs.4c02373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Qian C, Wang Z, Xiong Y, et al. Harnessing the deubiquitinase USP1 for targeted protein stabilization[J]. J Am Chem Soc, 2025, 147(17): 14564-14573. 10.1021/jacs.5c01662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117. Wang Z, Qian C, Xiong Y, et al. USP28-based deubiquitinase-targeting chimeras for cancer treatment[J]. J Am Chem Soc, 2025, 147(16): 13754-13763. 10.1021/jacs.5c01889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118. Chen B, Zhao HY, Li M, et al. SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2[J]. Cell Death Dis, 2022, 13(4): 403. 10.1038/s41419-022-04860-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119. Li SS, Sheng MJ, Sun ZY, et al. Upstream and downstream regulators of Klotho expression in chronic kidney disease[J]. Metabolism, 2023, 142: 155530. 10.1016/j.metabol.2023.155530. [DOI] [PubMed] [Google Scholar]
  • 120. Joung J, Konermann S, Gootenberg JS, et al. Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening[J]. Nat Protoc, 2017, 12(4): 828-863. 10.1038/nprot.2017.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121. Chen YL, Xue HA, Jin JP. Applications of protein ubiquitylation and deubiquitylation in drug discovery[J]. J Biol Chem, 2024, 300(5): 107264. 10.1016/j.jbc.2024.107264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122. Typiak M, Kulesza T, Rachubik P, et al. Role of klotho in hyperglycemia: its levels and effects on fibroblast growth factor receptors, glycolysis, and glomerular filtration[J]. Int J Mol Sci, 2021, 22(15): 7867. 10.3390/ijms22157867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123. Heijboer AC, Blankenstein MA, Hoenderop J, et al. Laboratory aspects of circulating-klotho[J]. Nephrol Dial Transplant, 2013, 28(9): 2283-2287. 10.1093/ndt/gft236. [DOI] [PubMed] [Google Scholar]
  • 124. Jurado-Fasoli L, Castillo MJ, Amaro-Gahete FJ. Dietary inflammatory index and S-klotho plasma levels in middle-aged adults[J]. Nutrients, 2020, 12(2): 281. 10.3390/nu12020281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125. Charrin E, Dabaghie D, Sen I, et al. Soluble Klotho protects against glomerular injury through regulation of ER stress response[J]. Commun Biol, 2023, 6(1): 208. 10.1038/s42003-023-04563-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126. Yoshida S, Wei XQ, Zhang GS, et al. Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function[J/OL]. J Clin Invest, 2021, 131(7): e143988[2025-05-10]. 10.1172/JCI143988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Zhu Y, Langhi Prata LGP, Wissler Gerdes EO, et al. Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans[J]. EBioMedicine, 2022, 77: 103912. 10.1016/j.ebiom.2022.103912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128. Donate-Correa J, Matos-Perdomo E, González-Luis A, et al. The value of klotho in kidney transplantation[J]. Transplantation, 2023, 107(3): 616-627. 10.1097/TP.0000000000004331. [DOI] [PubMed] [Google Scholar]

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