视网膜新生血管（RNV）性疾病是导致视力障碍和失明的主要原因之一，包括糖尿病视网膜病变、早产儿视网膜病变、视网膜静脉阻塞以及湿性年龄相关性黄斑变性等。成纤维细胞生长因子21（FGF21）作为一种多功能代谢调节因子，被发现对RNV形成具有显著抑制作用。本文系统综述了FGF21的生物学特性以及其在RNV性疾病中的分子调控机制和潜在治疗应用，旨在为开发基于FGF21的新型视网膜疾病治疗策略提供理论依 据。

视网膜新生血管（retinal neovascularization，RNV）性疾病是一组以病理性血管增生为特征的致盲性眼病，主要包括糖尿病视网膜病变（diabetic retinopathy，DR）、早产儿视网膜病变（retinopathy of prematurity，ROP）、湿性年龄相关性黄斑变性（wet age-related macular degeneration，wAMD）、视网膜静脉阻塞（retinal vein obstruction，RVO）等，其共同病理特征是异常血管形成，导致视网膜出血、渗出甚至牵引性视网膜脱离[1-2]，最终造成不可逆的视力损害。

目前，抗血管内皮生长因子（vascular endothelial growth factor，VEGF）药物是RNV性疾病临床治疗的主要手段[3]。然而，该疗法存在显著局限性。首先，耐药性问题日益突出，约30%患者对初始抗VEGF治疗无反应，超50%病例长期治疗仍存在视网膜积液[4-6]。部分患者会出现"过速现象"，在反复注射后逐渐丧失治疗效果[7-8]。其次，全身安全性问题不容忽视，Meta分析显示长期抗VEGF治疗与脑血管意外风险增加相关，还可能导致高血压、肾功能损害等系统性不良反应[9-11]。此外，长期VEGF抑制还可能引起视网膜缺血和黄斑萎缩等眼部并发症[12]。上述问题凸显了开发新型治疗策略的必要性。

成纤维细胞生长因子（fibroblast growth factor，FGF）21是FGF家族成员之一，最初被发现作为一种代谢调节激素，主要参与糖脂代谢平衡。近年研究表明，FGF21还具有抗氧化、抗炎和血管保护作用[13-14]。在眼科疾病领域，多项研究发现FGF21能够有效抑制病理性新生血管形成，其作用机制涉及调控血管生成因子、改善糖脂代谢以及发挥抗炎效应[15-18]。本文综述了FGF21在RNV性疾病中的作用及其调控机制，为克服当前抗VEGF治疗的局限性提供新的研究方 向。

1 FGF21的结构和生理功能

FGF21是一种由208个氨基酸组成的信号蛋白，属于FGF家族亚科19的成员。FGF21无肝素结合结构域，其与成纤维细胞生长因子受体（fibroblast growth factor receptor，FGFR）和共受体β-Klotho形成细胞表面受体复合物，作为内分泌因子进入血液循环并在靶组织中发挥作用[19]。

FGF21主要由肝脏、脂肪组织和胰腺分泌，但近年研究发现视网膜中也有FGF21的表达，其可能以自分泌或旁分泌方式调控视网膜微环境 [20- 21]。FGF21可以调节肝脏中的脂质和游离脂肪酸代谢，防止营养应激因素引起的脂肪中毒[22]。脂肪组织是FGF21的另一个重要靶点，FGF21具有脂肪分解和增加葡萄糖摄取等内分泌作用[23]。此外，肝FGF21可以穿透血脑屏障作用于神经元，减少甜食欲望和酒精偏好，并刺激水的摄入，以保持代谢平衡[24-25]。

2 FGF21影响RNV形成的作用机制

2.1 FGF21对血管生成因子的调节作用

RNV形成受多种血管生成因子调控，其中VEGF和血管生成素-2（angiopoietin-2，Ang2）是公认的关键驱动因子[1, 26]。研究表明，FGF21可同时调控这两条关键因子。在氧诱导视网膜病变模型中，过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor，PPAR）激动剂通过上调FGF21表达，抑制缺氧诱导因子-1α（HIF-1α）转录活性，进而下调VEGF表达[27]。多种RNV模型研究证实，FGF21能够显著提高脂联素（adiponectin，APN）水平[16]。APN不仅可降低VEGF水平，还能通过肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）依赖的方式抑制新内膜形成和巨噬细胞炎症[16, 28-29]。除调控VEGF外，FGF21还可靶向Ang2抑制酪氨酸激酶受体2受体信号通路，破坏血管壁的稳定性，同时增强内皮细胞对VEGF促血管生成作用的敏感性[26]。且FGF21可抑制Ang2表达，该作用已在心肌损伤模型中得到验 证[30-31]。

2.2 FGF21的抗炎和抗氧化应激作用

慢性炎症和氧化应激是RNV性疾病的重要病理机制[32-33]，而FGF21具有显著抗炎和抗氧化作用。在抗炎方面，FGF21以巨噬细胞为主要靶点，通过增强核因子E2相关因子2（Nrf2）活性和抑制核因子κB（NF-κB）信号通路，显著下调TNF-α和白介素1β（IL-1β）等促炎因子的表达[34-35]。在抗氧化应激方面，FGF21通过激活AMP活化蛋白激酶（AMP-activated protein kinase，AMPK）-线粒体复合物I组装因子NL1（MCONL1）-钙调磷酸酶（calcineurin）信号通路，促进转录因子EB（TFEB）的核转位，进而增强细胞的抗氧化应激能力[14]。上述机制可协同抑制RNV性疾病中的病理血管生成，并改善视网膜微环境。

2.3 FGF21对糖脂代谢的调节作用

糖脂代谢紊乱也会促进RNV形成，FGF21可以通过多途径调控糖脂代谢平衡。在胰腺β细胞中，FGF21通过激活PI3K/ Akt信号通路促进胰岛素表达和分泌，同时通过AMPK- ACC和PPARδ/γ信号通路减少胰岛细胞脂质积累，从而保护β细胞免于凋亡和功能障碍 [36-37]。且FGF21可通过调节AMPK-mTOR信号通路诱导胰腺自噬，这一机制在保护β细胞存活和功能方面发挥重要作用 [38]。在全身代谢调控方面，FGF21通过降低血清胰岛素水平和提高胰岛素敏感性来改善胰岛素抵抗状态，研究证实FGF21可通过FRS2- ERK1/2信号通路，有效减轻肥胖小鼠和3T3-L1脂肪前体细胞中与肥胖相关的炎症反应[39]。FGF21可干预糖脂代谢紊乱，为RNV性疾病提供治疗新策略。

3 FGF21在RNV性疾病中的作用及临床应用

3.1 糖尿病视网膜病变

DR是糖尿病微血管病变中一种重要的并发症，约有20%~30%糖尿病患者发生，其特征是血管生长停止或丢失引发的眼部缺氧与营养缺乏，进而病理性地导致新生血管过度生长[40-41]。

代谢研究显示，1型糖尿病患者外周血中的FGF21水平明显低于健康个体[42]。然而，在2型糖尿病合并视网膜病变的患者中，血清FGF21浓度显著上升，且其升高幅度与DR的临床分期呈正相关[43]，提示FGF21可能参与DR的发生发展过程。研究发现血清FGF21水平与DR风险之间存在U型关联，即过低或过高的FGF21水平均可能促进DR进展，表明低FGF21状态可能直接参与DR发病机制，而高FGF21水平可能是机体的代偿性反应[44]。动物模型研究进一步揭示了FGF21的多重保护作用，在链脲佐菌素诱导的1型糖尿病小鼠中，FGF21能有效调控血糖稳态[45]；在氧诱导的视网膜病变模型中，外源性FGF21给药可提升视网膜APN表达、降低TNF-α水平，并有效抑制病理性RNV形成[16]。此外，FGF21还具有肾脏保护作用，能够抑制糖尿病小鼠肾脏的脂质沉积并改善肾功能[46]。

3.2 早产儿视网膜病变

ROP是一种复杂的新生儿常见眼病，是全球范围内导致早产儿可预防性失明的主要原因之一 [47]。该疾病的发病机制可分为两个关键阶段：Ⅰ期表现为出生后生理性视网膜血管生长受抑，导致周边视网膜无血管化；随着视网膜组织不断成熟，无血管区能量需求增加导致局部缺氧和能量供应不足，从而触发血管增殖因子的释放，进而进展为II期病变，即病理性新生血管形成[48]。若未及时干预，可能最终导致视网膜脱离和永久性视力损害。

近年研究发现，FGF21在ROP发生发展中扮演重要角色。临床观察显示，早产儿出生后血清FGF21水平较足月儿显著降低[49]。动物实验证实，在高糖诱导的生理血管发育抑制的小鼠模型（模拟ROP I期病变）中，FGF21的视网膜和肝脏mRNA表达减少，外源性补充FGF21可通过增加APN水平和调节脂质代谢（特别是线粒体脂肪酸β氧化）来促进生理性视网膜血管生长，而FGF21的丧失则会进一步减弱生理性视网膜血管生长[50]。上述研究提示，FGF21可能通过改善I期病变的生理性视网膜血管生长抑制，进而预防II期病理性新生血管的形成。此外，循环中APN水平的升高与小鼠RNV减少有关，因此FGF21也可能通过调节APN水平，从而直接在II期ROP中发挥作用[16]。

3.3 年龄相关性黄斑变性

年龄相关性黄斑变性在临床上主要分为干性年龄相关性黄斑变性和wAMD两种亚型，其中wAMD的特征性病理改变是脉络膜新生血管（choroidal neovascularization，CNV）的形成[51]。但在病程中，氧化应激反应、慢性炎症状态以及组织缺氧等致病机制的参与，会导致Bruch膜结构损伤，同时破坏视网膜色素上皮细胞间的紧密连接，最终促使脉络膜来源的病理性血管向视网膜内生长，造成不可逆的视力损害[52]。

研究发现，FGF21作为代谢调节剂，对wAMD具有显著治疗潜力。在激光诱导的CNV小鼠模型中，FGF21给药不仅可有效抑制RNV与CNV形成，还能上调脉络膜-视网膜复合体中APN表达并降低TNF-α水平[16]。TNF-α通过促进内皮细胞出芽而加剧新生血管形成，FGF21可通过降低TNF-α水平来抑制CNV的发展[53]。在模拟晚期增殖性AMD的极低密度脂蛋白受体缺失小鼠模型中，FGF21类似物PF- 05231023治疗同样显示出显著疗效，既能减轻新生血管病变，又可调节APN和TNF-α水平[16]。上述研究为FGF21可作为治疗CNV的新型靶点提供了强有力的实验证据。

3.4 视网膜静脉阻塞

RVO是最常见的视网膜血管闭塞性疾病，其病理生理机制主要涉及静脉血流受阻导致的视网膜灌注不足。当静脉阻塞发生时，视网膜组织因缺血缺氧而激活HIF-1α信号通路，进而促进VEGF等促血管生成因子的过度表达[54]。这种病理性改变会引发视网膜血管渗漏、黄斑水肿以及异常新生血管形成等典型临床表现[55-56]。抗VEGF药物治疗通过中和过量的VEGF来改善血管通透性和抑制新生血管生成，已成为RVO的一线治疗方案[57]。

研究发现，FGF21在RVO治疗中展现出多靶点调控优势。在分子机制层面，FGF21能够直接抑制HIF-1α的转录活性，从而下调VEGF的表达水平[27]。该调控作用不仅减少了病理性血管渗漏和新生血管形成，还可能避免长期抗VEGF治疗导致的血管萎缩等副作用。其次，FGF21通过调节NF-κB信号通路，显著降低TNF-α、IL-1β等促炎因子的释放，对于改善缺血再灌注损伤后的炎症微环境尤为重要[34]。

4 FGF21的治疗潜力与展望

RNV性疾病作为多种致盲性眼病的共同病理特征，其治疗一直是眼科领域的重大挑战。近年研究发现，FGF21在大量临床前研究中被证实能显著抑制病理性新生血管形成，展现出良好的治疗潜力。

与目前一线疗法抗VEGF治疗相比，FGF21的优势在于其多靶点作用特性。FGF21不仅能下调促血管生成因子表达[27, 30]，还通过APN- TNF-α通路抑制新生血管形成[16]。同时，FGF21可能以自分泌或旁分泌方式参与局部微环境调控，降低炎症因子水平和调节糖脂代谢来干预RNV的重要病理过程[34-36, 39]。

然而，将FGF21成功转化到临床应用仍面临诸多挑战，最突出的问题是FGF21的生理调控和功能存在显著的种属差异。在啮齿类动物中，禁食或生酮饮食能显著上调FGF21表达[58]；而人类仅长期禁食可诱导FGF21升高，且生酮饮食反而会降低其水平[59]。这种差异也体现在治疗效果上，FGF21在糖尿病小鼠和猴模型中能显著降低血糖并改善葡萄糖代谢[60-62]，但在2型糖尿病患者的临床试验中却未能达到预期的血糖控制效果 [63]。此外，FGF21的多效性可能带来复杂的生物学效应。临床研究数据显示，FGF21可引起骨质流失，但不同研究结果存在差异[64-66]。动物实验提示FGF21可能促进肌肉萎缩，但在人体中的临床相关性尚待进一步证实[67]。上述因素为FGF21的临床应用带来了挑战。

5 结语

FGF21有望成为RNV性疾病的新型治疗选择，特别是对抗VEGF治疗耐药的患者。未来研究需要重点关注以下几个方向：开发视网膜靶向递送系统，提高药物靶向性并减少副作用；探索与抗VEGF药物联合治疗策略具有重要前景，通过多靶点干预不同病理机制，可能实现协同增效；构建更贴近人类疾病特征的动物模型，可显著增强临床前研究的转化价值和预测效力。

伦理声明：不适用

作者贡献：框架拟定和论文修改：杨安怀、肖璇、刘航；论文撰写：石若冰、朱方媛；经费支持：肖璇

数据获取：不适用

利益冲突声明：无

致谢：不适用

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