Eblasakimab

近期，国内科研界喜事连连，吴玉章、葛均波、袁钧瑛等多位院士团队相继在国际顶级期刊发表重磅研究成果。这些成果横跨免疫调控、肿瘤治疗、心血管疾病、代谢医学、食品科学等多个领域，不仅填补了相关领域的研究空白，更有望推动临床治疗与产业应用的革新，展现了中国科研的强劲创新活力。 免疫耐受新蓝图：Treg 细胞的临床转化之路 该研究由中国科学院上海有机化学研究所袁钧瑛院士、邹呈雨研究员联合多国学者共同完成，论文标题为《Next steps in regulatory T cells: Biology and clinical application》。 免疫相关疾病的治疗长期面临着平衡免疫抑制与免疫耐受的难题，传统疗法往往难以精准调控免疫系统。随着调节性 T 细胞被证实是维持免疫稳态的核心力量，如何将这一基础发现转化为临床疗法成为领域内的关键方向。 研究旨在系统梳理调节性 T 细胞生物学的最新进展，明确其临床转化的核心挑战与发展路径。团队通过整合近年基础研究数据与多项临床试验结果，深入分析调节性 T 细胞的稳定性、抑制功能及代谢调控机制。 研究结论显示，调节性 T 细胞可作为 “活体药物”，通过重建免疫耐受与修复受损组织发挥治疗作用。低剂量 IL-2 联合传统药物治疗渐冻症时，能显著降低特定亚组患者的死亡率；过继性 T 细胞转移在预防移植物抗宿主病中效果显著，CAR-Treg 细胞的早期探索也展现出潜力。 这一成果为自身免疫疾病与神经退行性疾病的治疗提供了全新范式，未来通过优化精准耐受策略，有望让调节性 T 细胞疗法成为像免疫检查点抑制剂一样具有变革性的治疗手段。 CAR-T 新突破：鞘内给药攻克复发高级别胶质瘤 苏州大学附属第四医院黄煜伦主任医师、陆军军医大学吴玉章院士等团队联合完成该研究，论文标题为《Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial》。 复发高级别胶质瘤预后极差，传统手术、放化疗效果有限。CAR-T 细胞疗法在血液肿瘤中成效显著，但在脑部实体瘤治疗中，面临着肿瘤浸润困难、免疫抑制微环境及移植物抗宿主病等多重障碍，异体 CAR-T 的临床应用更是亟待突破。 研究目标是开发一种安全有效的异体 CAR-T 疗法，用于治疗复发高级别胶质瘤。团队借助 CRISPR-Cas9 基因编辑技术对异体 T 细胞进行改造，靶向敲除内源性 T 细胞受体与 HLA I 类分子编码基因，同时导入 IL-13Rα2 特异性 CAR 结构。 临床前研究通过细胞毒性检测、动物模型移植实验验证了细胞的靶向杀伤能力与安全性，随后开展首次人体单中心开放标签 I 期临床试验，采用腰椎穿刺鞘内注射方式给药。结果显示，5 例入组患者中 1 例完全缓解，3 例部分缓解，未出现三级及以上严重不良事件，主要毒性为轻度发热、缺氧与呕吐。 这一突破为实体瘤治疗提供了全新思路，鞘内给药方式解决了脑部肿瘤的靶向递送难题，基因编辑技术降低了异体 CAR-T 的免疫排斥风险，为后续更大规模临床试验与疗法优化奠定了基础。 心血管疾病新靶点：组蛋白乳酸化的调控机制 复旦大学附属中山医院葛均波院士、孙爱军教授团队完成该研究，论文标题为《Histone Lactylation–Mediated Metabolic Remodeling in Vascular Smooth Muscle Cells Aggravates Aortic Aneurysm and Dissection by Promoting Lactate Accumulation》。 主动脉瘤与夹层是致死率极高的心血管急症，目前缺乏有效的药物治疗手段。血管平滑肌细胞的表型转换与代谢重编程被认为是疾病进展的关键，但其中的表观遗传调控机制尚未明确。 研究聚焦组蛋白乳酸化这一新型表观遗传修饰，探究其在主动脉瘤与夹层发生发展中的作用及调控机制。团队采用临床样本分析、动物模型构建、细胞培养、CUT&Tag 测序、分子对接、免疫共沉淀等多种技术，系统解析组蛋白乳酸化对血管平滑肌细胞代谢与表型的影响。 研究发现，主动脉瘤与夹层患者的血管组织中，组蛋白 H4 赖氨酸 16 位点乳酸化水平显著升高，且与乳酸积累呈正相关。赖氨酸转移酶 7 是催化这一修饰的关键酶，其通过激活 PDK1 转录形成 “组蛋白乳酸化 - PDK1 - 乳酸” 正向反馈循环，驱动血管平滑肌细胞向合成炎症表型转换。抑制 PDK1 或赖氨酸转移酶 7 可有效减轻血管病变，血乳酸与 H4K16la 有望成为疾病诊断的生物标志物。 该研究揭示了代谢与表观遗传交叉调控的新机制，明确了 PDK1 与赖氨酸转移酶 7 两个潜在治疗靶点，为心血管疾病的精准防治提供了科学依据。 肝病干预新发现：脂质诱导颗粒的抗纤维化作用 海军军医大学侯晋教授、曹雪涛院士团队完成该研究，论文标题为《Lipid-induced granules in hepatocytes alleviate liver fibrosis》。 代谢功能障碍相关脂肪性肝病是全球高发的肝脏疾病，其进展至肝纤维化阶段后治疗难度大幅增加。肝细胞应激状态下的无膜细胞器形成与功能调控，成为解析肝病进展机制的重要方向，但脂肪变性肝细胞中是否存在新型功能性无膜细胞器尚不明确。 研究旨在寻找脂肪变性肝细胞中参与肝纤维化调控的新型无膜细胞器，并阐明其作用机制。团队通过筛选 DDX 家族蛋白，结合液液相分离实验、细胞功能验证、临床样本检测等方法，探究新型细胞器的形成条件与调控路径。 研究首次发现，花生四烯酸代谢物可诱导肝细胞中 DDX49 发生液液相分离，形成脂质诱导颗粒。这种新型无膜细胞器通过招募 m5C 修饰的 Timp2 mRNA 及其结合蛋白 YBX1，抑制 Timp2 的翻译过程，从而反馈抑制肝纤维化进展。临床样本分析显示，脂质诱导颗粒的丰度与肝纤维化程度呈负相关。 这一发现为肝纤维化的治疗提供了全新靶点，通过调控脂质诱导颗粒的形成或功能，有望开发出新型抗纤维化疗法，为代谢相关肝病的治疗开辟新路径。 食品风味新机制：液熏虹鳟鱼的脂质转化密码 中国海洋大学徐杰教授、薛长湖院士团队完成该研究，论文标题为《Unraveling the flavor evolution mechanism in liquid-smoked rainbow trout through integrated lipidomics and flavoromics》。 虹鳟鱼作为优质冷水鱼，其液熏制品因独特风味广受市场欢迎，但液熏过程中脂质转化与风味形成的关联机制尚未明确，制约了产品品质的精准优化。 研究聚焦液熏虹鳟鱼加工中的风味演变机制，旨在解析脂质水解与氧化对风味物质生成的调控作用。团队设置鲜鱼、盐渍、不同时长液熏等五个加工阶段，采用脂质组学、风味组学联用技术，结合电子鼻检测与感官评价，系统分析脂质组成、氧化指标与挥发性有机化合物的动态变化。 实验数据表名，液熏加工显著促进脂质水解与氧化，甘油三酯、磷脂含量下降，溶血磷脂含量升高，C18:2、C18:1 等脂肪酸成为关键风味前体。脂质氧化生成的己醛、庚醛等赋予产品 “脂香”，液熏液中的酚类物质形成 “烟香”，二者协同构建了产品的核心风味。庚醛、己醛等被确定为风味标志物，与特定脂质呈显著差易。 该研究为液熏水产品的工艺优化提供了理论支撑，通过精准调控脂质转化过程，可实现产品风味与品质的定向提升，助力水产加工业的高质量发展。 肺癌耐药新解析：Linc01833 的 ferroptosis 调控作用 温州医科大学李校堃院士、崔日教授团队完成该研究，论文标题为《Linc01833 drives gemcitabine resistance in non-small cell lung cancer by shielding SLC7A11 from WWP1-mediated ubiquitination and inhibiting ferroptosis》。 吉西他滨是治疗非小细胞肺癌的常用化疗药物，但耐药性的产生严重影响治疗效果。长链非编码 RNA 在肿瘤耐药中发挥重要作用，而 Linc01833 对吉西他滨耐药的调控机制及与铁死亡的关联尚不明确。 研究旨在揭示 Linc01833 在非小细胞肺癌吉西他滨耐药中的作用及分子机制。团队通过耐药细胞系构建、基因沉默与过表达、免疫沉淀、泛素化检测、铁死亡标志物分析等方法，系统探究 Linc01833 对肿瘤细胞存活与药物敏感性的影响。 研究发现，Linc01833 在吉西他滨耐药的非小细胞肺癌细胞中表达显著升高。其通过与 SLC7A11 结合，阻止 WWP1 介导的泛素化降解，增强 SLC7A11 的稳定性，进而抑制肿瘤细胞铁死亡，最终导致耐药性产生。沉默 Linc01833 可恢复肿瘤细胞对吉西他滨的敏感性。 这一发现为逆转肺癌化疗耐药提供了新靶点，通过靶向 Linc01833 或调控 SLC7A11 相关的铁死亡通路，有望开发出联合治疗策略，提升非小细胞肺癌的治疗效果。 病毒增殖新机制：TSWV 的糖酵解劫持策略 贵州大学宋宝安院士团队完成该研究，论文标题为《Tomato spotted Wilt Virus Reprogrammes Host Glycolysis to Facilitate Proliferation by a Phase-Separated Co-Aggregate of Nucleocapsid Protein and Phosphoglycerate Kinase》。 番茄斑萎病毒是危害严重的植物病毒，给农业生产造成巨大损失。目前对该病毒调控宿主代谢以促进自身增殖的分子机制了解有限，缺乏作用机制新颖的抗病毒药剂。 研究旨在阐明番茄斑萎病毒劫持宿主代谢的分子机制，为开发新型抗病毒药物提供靶点。团队通过蛋白质互作筛选、相分离实验、酶活性检测、小分子化合物筛选等方法，探究病毒核衣壳蛋白与宿主蛋白的相互作用及功能影响。 研究发现，番茄斑萎病毒的核衣壳蛋白可与宿主糖酵解关键激酶 NbPGK 形成相分离凝聚体，从而重编程宿主糖酵解通路。糖酵解产生的 ATP 既为病毒复制提供能量，又以非酶促方式增强凝聚体形成，促进病毒增殖。筛选得到的小分子化合物 F10 可靶向结合核衣壳蛋白，抑制其与 NbPGK 的相互作用，展现出优异的抗病毒活性。 该研究揭示了病毒利用宿主代谢的全新策略，为抗病毒药物研发提供了新靶点与先导化合物，对保障农业生产安全具有重要意义。 免责申明：本文来源网络，仅用于学术分享，文章、图片等版权归原作者享有，如涉著作权事宜请联系小编修改或删除。 往期推荐  仅开放10个免费方案设计名额🚨添加小编立即锁定 从博士后到副教授，论文争议如影随形！“杰出女作者” 学术污点终曝光 生男生女概率不随机？《科学》子刊：这些家庭或一直生同性别孩子，潜在因素找到了 史上引用量第一的论文 中科院分区表回应争议：中国学术期刊评价体系经得起推敲！ Tips：点击“阅读原文”免费领取国自然解密课程！

作者：修梦晨 美工：何国红 罗真真 排版：马超 一、引言 特应性皮炎（Atopic Dermatitis, AD）是一种常见的慢性、复发性、炎症性皮肤病，以皮肤敏感干燥、剧烈瘙痒、出现局限性或泛发性湿疹样皮损为主要特征，常伴随过敏性鼻炎、哮喘等其他特应性疾病，严重影响患者生活质量。根据疾病严重程度可分为轻度、中度、重度三级。特应性皮炎在全球范围内影响广泛。流行病学数据显示，儿童患病率约为20%，青少年约为15%，成人约为10%。2019年，全球特应性皮炎患者人数约为6.49亿，预计到2030年，患者规模将扩大至7.55亿。 作为全球疾病负担第一的皮肤病，AD的药物市场需求持续旺盛。2023年已达112.3亿美元，并呈现持续增长趋势，预计将从2024年的118.1亿美元以5.12%的复合年增长率增长至2032年的176.1亿美元（图1）。虽增速略有放缓，但行业整体仍处于持续扩张阶段。 ▲ 图1 全球特应性皮炎市场规模（十亿美元） 二、AD的发病机制：从屏障缺陷到免疫紊乱的多环节调控 特应性皮炎的发病机制是一个由遗传、免疫和环境因素共同参与的复杂过程。遗传因素构成其重要基础，典型表现为皮肤屏障相关基因功能异常，例如FLG基因突变可导致丝聚蛋白的表达降低，进而破坏表皮屏障的完整性，增加经表皮水分流失并改变皮肤表面pH值，从而使皮肤更易受到外界刺激和过敏原侵袭。 在免疫层面（图2），皮肤屏障受损使外来过敏原更容易进入皮肤内部并激活免疫相关细胞，尤其是树突状细胞和角质形成细胞，角质形成细胞通过释放胸腺基质淋巴细胞生成素（TSLP）、IL-33、IL-25等炎症因子，激活树突状细胞，诱导其成熟并上调OX40L等共刺激分子，同时强化其Th2极化功能；成熟树突状细胞迁移至淋巴结，通过抗原呈递、OX40L-OX40结合以及分泌少量IL-4，驱动初始CD4⁺T细胞分化为Th2细胞。随后，Th2细胞迁移至皮肤皮损部位，通过分泌IL-4、IL-13、IL-5等细胞因子，介导IgE水平升高、瘙痒及炎症。此外，在疾病的不同阶段，Th1、Th17及Th22等T细胞亚群也参与调控，共同促进慢性炎症延续及皮肤增厚等病理改变。 ▲ 图2 特应性皮炎的病理生理学 环境因素则在遗传与免疫基础上进一步推动疾病的发展与加重，包括空气污染、低湿度气候、城市化生活方式以及心理压力等。其中，污染物和干燥环境会直接破坏皮肤屏障并诱导氧化应激，使皮肤更容易发生炎症。多种环境刺激的叠加作用既可触发疾病，也会加重原本已经受损的皮肤屏障和免疫反应，形成恶性循环。因此，特应性皮炎是一种由遗传基础、免疫失衡以及环境诱因共同作用而形成的复杂多因素疾病。 三、AD的治疗：从传统疗法到精准靶向治疗 随着对AD发病机制认识的不断深化，AD治疗已从早期的糖皮质激素、环孢素等非特异性药物，逐步发展为局部靶向药物（如克立硼罗）和系统性靶向药物（如度普利尤单抗等生物制剂、JAK抑制剂等小分子靶向药），覆盖人群也从成人逐步拓展至儿童乃至婴幼儿，治疗精准性与安全性均持续提升，实现了从“非特异性传统疗法”向“精准靶向疗法”的升级迭代（图3）。 ▲ 图3 特应性皮炎治疗药物的发展历程 01 传统治疗 ▶ 非药物治疗：非药物治疗是特应性皮炎的一线治疗策略。采用合理的皮肤清洁策略，并持续使用保湿剂、润肤剂，可减少经表皮失水量（TEWL）并增强皮肤屏障的锁水能力，防止过敏原及微生物入侵。 ▶ 外用药物治疗：对于非药物治疗无效的难治性患者，需升级至外用药物治疗。该治疗类别包括处方级保湿剂（按医疗器械监管）、外用糖皮质激素（TCS）、外用钙调神经磷酸酶抑制剂（TCIs）等。其中，TCS是目前AD传统治疗的一线药物，其通过与胞质内糖皮质激素受体（GR）结合发挥抗炎作用。目前，全球已有10款治疗AD的TCS药物获批上市，例如氢化可的松软膏，糠酸莫米松。TCIs则是通过特异性抑制钙调神经磷酸酶的活性，发挥阻断T淋巴细胞活化的作用，目前有2款治疗AD的TCIs获批上市，分别是他克莫司和吡美莫司。尽管外用药物是标准治疗手段，但由于其疗效有限，且可能引发皮肤变薄、给药部位疼痛、灼烧感及刺痛等问题，因此，仍有相当比例的中重度AD患者需要联合系统治疗。 ▶ 小分子免疫抑制剂治疗：对于局部外用药物疗效不佳的重度特应性皮炎患者，可采用环孢素 A（CsA）、甲氨蝶呤（MTX）、硫唑嘌呤（AZA）、吗替麦考酚酯（MMF）等小分子免疫抑制剂进行治疗。然而，免疫抑制剂类药物长期全身使用可能带来一系列不良反应，如胃肠道不适、肝肾功能损伤、骨髓抑制和血栓等。 ▶ 光疗：当一线局部治疗与传统全身性治疗效果不佳、存在禁忌症或患者耐受性较差时，光疗是特应性皮炎临床公认的二线干预方案。根据美国皮肤病学会（AAD）指南，窄谱中波紫外线（NB-UVB）光疗适用于中重度AD患者，它能诱导DNA光产物生成，干扰转录并抑制增生性表皮特有的快速细胞分裂；此外，光疗引发的氧化应激还能抑制抗原提呈及树突状细胞介导的T细胞活化。尽管光疗在AD治疗中具有确切疗效，但也存在诸多局限性，如轻则出现光化性损伤、红斑，重则可能诱发黑色素瘤、白内障等严重病变。 综上，由于传统治疗方式缺乏精准靶向性且易引发不良反应，因此难以满足临床对“低毒高效”的治疗需求。随着AD发病机制研究的不断深入，尤其是Th2炎症、细胞因子网络及关键信号通路在疾病发生发展中的核心作用逐渐明确，靶向关键分子和通路的精准治疗策略应运而生，为AD治疗开辟了更加针对性和高效的新途径。 02 系统性靶向治疗 ▶ 生物制剂：对于经局部治疗后病情仍难以控制的中重度特应性皮炎患者，需采用生物制剂（如单克隆抗体）进行系统性治疗干预。而这类抗体药物的临床应用，离不开从靶点发现到技术落地的持续演进：自1990s–2000s年间IL‑4、IL‑13等核心靶点被发现以来，AD的免疫发病机制逐渐明确。2017年，度普利尤单抗（Dupilumab）的上市标志着AD大分子药物时代的开启，实现了从“靶点探索”到“临床验证”的跨越。随后，AD抗体药物逐步进入“多靶点布局、全球及本土产品商业化”阶段。目前，IL‑4Rα/IL‑13靶点已形成成熟管线，而OX40等新靶点药物也进入临床后期研发阶段。本土药企的自研产品，如司普奇拜单抗，也在2024年后实现上市突破。整体管线正快速发展，朝着“覆盖更多炎症通路、适配不同患者群体”的方向推进（图4）。 ▲ 图4 特应性皮炎抗体药物的发展历程（Ⅲ期临床及以上阶段，2025年12月） 抗体药物通过特异性靶向AD致病相关的关键免疫细胞及细胞因子，阻断其介导的炎症反应通路与信号转导，从而有效抑制由此引发的皮肤屏障功能障碍及瘙痒反应，实现精准治疗。该类药物疗效显著且安全性较高，能精准调控病理免疫通路，为中重度患者提供了全新的治疗选择。经统计，目前有五款治疗AD的单克隆抗体药物获批上市（表1），分别是靶向IL13的来金珠单抗（Lebrikizumab）和曲罗芦单抗（Tralokinumab）、靶向IL31Rα奈莫利珠单抗（Nemolizumab）、靶向IL-4Rα的司普奇拜单抗（Spesolimab）和度普利尤单抗（Dupilumab）。度普利尤单抗作为首个靶向白细胞介素-4受体α亚基（IL-4Rα）的全人源化IgG4型单克隆抗体，2024年，该药全球销售额高达130.72亿欧元（约141亿美元），展现出强劲的市场增长势头，超越艾伯维的修美乐，跃升为自身免疫领域新一代的“药王”。 ▼ 表1 全球已上市特应性皮炎单抗药物总结 （2025年12月） 此外，我们对AD领域在研抗体药物所覆盖的49个靶点进行了系统梳理与统计（图5）。其中既包括IL-4Rα、IL-13、IL-31Rα等已有上市药物对应的成熟靶点，也涵盖了TSLP、OX40L、OX40等近年来逐步进入研发视野的新兴靶点。 ▲ 图5 特应性皮炎抗体药物靶点在研项目分布图 （2025年12月） (1) IL-4/IL13/IL4Rα/IL13α1 IL-4与IL-13作为特应性皮炎发病机制中核心的Th2型细胞因子，具有高度同源性且共享IL-4Rα受体亚基，其产生以活化的Th2细胞为主，2型固有淋巴细胞（ILC2s）、肥大细胞、嗜碱性粒细胞等固有免疫细胞也可少量分泌。二者通过结合靶细胞表面的IL-4Rα/IL-13Rα异二聚体受体，激活JAK/STAT等下游信号通路（图6），促进初始CD4+ T细胞向Th2细胞极化、抑制Th1/Th17细胞分化，刺激B细胞产生IgE抗体。基于其关键病理作用，靶向IL-4/IL-13通路的治疗已成为AD精准治疗的核心策略，度普利尤单抗、司普奇拜单抗等IL-4Rα靶向药物可同时阻断二者信号，曲罗芦单抗、来金珠单抗等IL-13特异性拮抗剂也展现出显著疗效，为中重度AD患者提供了重要治疗选择。 (2) IL31/IL31Rα IL-31主要由Th2细胞产生，是特应性皮炎中瘙痒-搔抓循环的关键驱动因子。其作用机制为：通过与免疫细胞(如活化的巨噬细胞、树突状细胞)、角质形成细胞和皮肤周围神经表面的IL-31受体（IL-31Rα/OSMRβ异二聚体组成）特异性结合，激活下游JAK/STAT、MAPK等信号通路（图6）。代表药物有奈莫利珠单抗（Nemolizumab），其通过特异性结合IL-31Rα，阻断IL-31介导的信号传导。 ▲ 图6 特应性皮炎Th2型免疫应答中的JAK-STAT信号通路 (3) TSLP 胸腺基质淋巴细胞生成素（TSLP）主要由角质形成细胞在受到外界刺激（如过敏原、病原体或物理损伤）后分泌释放，能够有效激活皮肤局部树突状细胞，增强其抗原呈递能力并诱导其表达共刺激分子，进而促进初始T淋巴细胞活化并向Th2表型极化，驱动以IL-4、IL-13等2型细胞因子为核心的炎症应答（图7）。在特应性皮炎患者中，血清及皮损局部组织内TSLP水平均显著升高，其表达强度与疾病活动度及严重程度呈正相关。代表药物有替泽普单抗（Tezepelumab），二期临床已经展现出了显著的疗效。 ▲ 图7 TSLP在特应性皮炎发病机制中的作用 (4) OX40/OX40L OX40受体及其配体OX40L均属于肿瘤坏死因子（TNF）超家族成员，OX40受体主要表达于T细胞表面，而OX40L的表达范围更为广泛，包括抗原呈递细胞、内皮细胞及气道平滑肌细胞等，二者的相互作用可介导T细胞活化、分化及存活（图8）。在AD皮损组织中，表达OX40的效应T细胞数量增加。抗OX40单克隆抗体通过阻断OX40与其配体OX40L的结合，抑制下游信号通路，从而减少T细胞的增殖、存活及记忆性T细胞的形成，并降低包括Th1、Th2、Th22和Th17在内的多个T细胞亚群功能，缓解疾病慢性化进程。目前国外有多款OX40/OX40L单抗正在研发，包括罗卡替珠单抗（Rocatinlimab）、替拉珠单抗（Telazorlimab）及阿莫利珠单抗（Amlitelimab）等，从已公布的临床研究数据来看，该类靶向药物在治疗终止后仍能维持持续的临床应答效应，为降低AD患者停药后的疾病复发风险提供了潜在的治疗策略。 ▲ 图8 OX40/OX40L在特应性皮炎发病机制中的作用 未来，AD生物制剂的治疗将围绕“多靶点协同抑制、分子形式迭代、个体化分段管理”形成核心趋势：一是开发双靶或三靶药物（如同时阻断IL-4Rα与IL-31Rα的双特异性抗体）以覆盖更复杂的炎症通路并提高整体疗效；二是持续挖掘新的治疗靶点（例如IL-22、IL-33等）以拓展治疗管线；三是聚焦长效化与给药优化，研发长效制剂（如半衰期延长型抗IL-13单克隆抗体APG777）及抗体融合蛋白、纳米抗体等新型分子，拓展皮下注射长效剂型与局部外用制剂，减少给药频次，提升特殊人群依从性；四是推动精准医学与个体化治疗，通过生物标志物或表型分型指导疗法选择，从而提高治疗匹配度和效果。 03 小分子靶向药物 抗体类生物制剂虽实现了精准靶向治疗，但仍存在给药不便（需注射）、靶点覆盖局限（多聚焦细胞外单一通路）及价格偏高的短板，无法满足部分患者（如对生物制剂应答不佳者）的治疗需求；而小分子靶向药物可穿透皮肤屏障或直接进入细胞内调控JAK-STAT等多通路，适配疾病复杂发病机制，且其化学合成工艺成熟、成本更低，口服或外用剂型大幅提升用药便捷性与可及性，因此成为特应性皮炎精准治疗体系的重要补充。 (1) Janus激酶抑制剂（JAKi） 是一类靶向JAK-STAT通路的新兴治疗药物，通过竞争性结合JAK的ATP结合位点，阻止JAK自身磷酸化与激活，从而中断JAK-STAT通路传导，减少促炎因子产生。目前，有六种JAKi已获批上市（表2），分别是三种口服JAKi：巴瑞替尼、阿布昔替尼及乌帕替尼，用于治疗中重度AD患者；以及三种外用JAKi：德戈替尼、艾玛昔替尼、芦可替尼，用于治疗轻度至中度AD患者。但需注意的是，口服JAKi作为具有全身生物利用度的小分子药物，其潜在不良反应风险是临床应用中需重点考量的问题。FDA目前要求所有JAK抑制剂的药品说明书中均须纳入黑框警告，明确提示该类药品可能伴随严重感染、恶性肿瘤、主要不良心血管事件、血栓形成等风险。 (2) 磷酸二酯酶4抑制剂（PDE4i） 能选择性抑制PDE4，升高cAMP水平，从而下调促炎细胞因子的产生。目前有3款治疗AD的PDE4i获批上市（表2），分别是克立硼罗、地法米司特、罗氟司特。其中，外用PDE4i的不良反应以局部表现为主，多为用药部位出现烧灼感、刺痛感、红斑、脱屑及皮肤干燥等症状。多发生在治疗初期，程度多为轻度至中度，随皮肤适应后逐渐缓解。 (3) 芳香烃受体（AHR）调节剂 通过激活AHR，调控角质形成细胞分化和屏障修复相关基因（如丝聚蛋白）表达，从而抑制Th2/Th22型炎症反应，改善皮肤屏障并减轻炎症，代表药物有本维莫德乳膏（表2）。但目前临床数据有限，潜在的长期风险仍需进一步验证。 ▼ 表2 全球已上市特应性小分子靶向药物总结 （2025年12月) 四、总结及展望 特应性皮炎作为一种与免疫失衡、遗传易感性及环境因素密切相关的慢性炎症性皮肤病，其临床管理与机制研究已取得阶段性突破，为后续研究奠定了坚实基础。当前AD治疗体系已形成“分层干预”的核心框架：轻中度患者以局部治疗为主，如外用糖皮质激素和钙调磷酸酶抑制剂，通过局部抗炎与免疫调节控制皮损；中重度或外用治疗不佳的难治性患者则可采用生物制剂、JAK抑制剂等靶向药物，实现全身性炎症的精准调控。基于生物制剂的靶向优势与特应性皮炎的异质性病理特征高度契合，以及单一药物应答不足时，不同靶向药物的联合/混合疗法，未来数年，生物制剂将在特应性皮炎治疗市场中占据主导地位。 尽管现有治疗已显著改善患者预后，但AD的复杂性仍决定了研究需向更深层次推进。未来研究应聚焦三大核心方向：其一，开展跨人群的长期结局追踪研究，明确现有及新型治疗手段在不同年龄、遗传背景患者中的疗效稳定性与安全性差异，为临床用药的个体化选择提供循证依据；其二，基于AD的遗传易感性特征，深化基因组学与转录组学研究，构建以个体分子图谱为核心的个性化治疗模型；其三，推动纳米技术在给药系统中的应用，依托纳米颗粒的靶向递送特性，解决传统药物皮肤渗透不足、全身不良反应显著等问题，通过提升药物生物利用度与剂量可控性，优化治疗效能。 综上，AD研究已从“机制阐释”迈入“精准干预”的新阶段。随着多学科交叉技术的融合应用与循证医学证据的不断积累，未来AD治疗将实现“机制精准解析、方案个性化定制、给药高效安全”的目标，为患者提供更优质的临床获益。 Sanyou 10th Anniversary: Atopic Dermatitis: From Immune Dysregulation to Precision Targeted Therapy Revolution 1. Introduction Atopic dermatitis (AD) is a common chronic, relapsing inflammatory skin disease characterized by dry and sensitive skin, intense pruritus, and localized or generalized eczematous lesions. It is frequently associated with other atopic disorders such as allergic rhinitis and asthma, severely impairing patients’ quality of life. According to disease severity, AD is generally classified into mild, moderate, and severe forms. AD represents a significant global health burden. Epidemiological studies indicate a prevalence of approximately 20% in children, 15% in adolescents, and 10% in adults worldwide. In 2019, the global number of patients with AD was estimated at approximately 649 million, and this figure is projected to rise to 755 million by 2030. As the leading skin disease in terms of global disease burden, AD continues to generate strong demand in the pharmaceutical market. In 2023, the global AD market reached USD 11.23 billion and is expected to grow from USD 11.81 billion in 2024 to USD 17.61 billion by 2032, at a compound annual growth rate (CAGR) of 5.12% (Figure 1). Although the growth rate has moderately slowed, the market remains in a sustained expansion phase. ▲ Figure 1. Global atopic dermatitis market size (USD billions) 2. Pathogenesis of AD: Multilevel Regulation from Barrier Dysfunction to Immune Dysregulation The pathogenesis of AD is a complex, multifactorial process involving genetic susceptibility, immune dysregulation, and environmental triggers. Genetic factors constitute a critical foundation of disease development, most notably abnormalities in genes related to skin barrier integrity. For example, mutations in the FLG gene lead to reduced filaggrin expression, compromising epidermal barrier function, increasing transepidermal water loss (TEWL), and altering skin surface pH. These changes render the skin more vulnerable to external irritants and allergens. At the immunological level (Figure 2), barrier disruption facilitates the penetration of exogenous allergens into the skin, activating immune cells such as dendritic cells and keratinocytes. Activated keratinocytes release epithelial-derived cytokines, including thymic stromal lymphopoietin (TSLP), IL-33, and IL-25, which promote dendritic cell activation, maturation, and upregulation of costimulatory molecules such as OX40L. These processes enhance Th2 polarization capacity. Mature dendritic cells migrate to draining lymph nodes, where they drive naïve CD4⁺ T-cell differentiation into Th2 cells through antigen presentation, OX40L–OX40 interaction, and low-level IL-4 secretion. Subsequently, Th2 cells migrate back to lesional skin and secrete IL-4, IL-13, and IL-5, leading to elevated IgE production, pruritus, and inflammation. In different disease stages, other T-cell subsets—including Th1, Th17, and Th22—also participate in disease modulation, collectively contributing to chronic inflammation and epidermal hyperplasia. ▲ Figure 2. Pathophysiology of atopic dermatitis Environmental factors further exacerbate disease development on this genetic and immunological background. Air pollution, low-humidity climates, urban lifestyles, and psychological stress can directly impair the skin barrier and induce oxidative stress, thereby amplifying inflammatory responses. The combined effects of multiple environmental insults can both initiate disease onset and aggravate pre-existing barrier and immune dysfunction, forming a self-perpetuating vicious cycle. Therefore, AD is best understood as a complex disease driven by the interplay of genetic predisposition, immune imbalance, and environmental triggers. 3. Treatment of AD: From Conventional Therapies to Precision Targeted Therapies With increasing insight into AD pathogenesis, therapeutic strategies have evolved from nonspecific immunosuppressive agents—such as topical corticosteroids and cyclosporine—to targeted topical agents (e.g., crisaborole) and systemic targeted therapies, including biologics (e.g., dupilumab) and small-molecule inhibitors (e.g., JAK inhibitors). Treatment indications have expanded from adults to children and even infants, with continuous improvements in precision and safety. This evolution marks a paradigm shift from “nonspecific conventional therapy” to “precision targeted therapy” (Figure 3). ▲ Figure 3. Evolution of therapeutic agents for atopic dermatitis 01 Conventional Therapies ▶ Non-pharmacological therapy: Non-pharmacological management represents the first-line strategy for AD. Appropriate skin cleansing combined with consistent use of moisturizers and emollients reduces TEWL, enhances skin hydration, and reinforces barrier function, thereby preventing allergen and microbial penetration. ▶ Topical pharmacotherapy: For patients with inadequate response to non-pharmacological measures, topical pharmacological treatments are required. These include prescription emollients (regulated as medical devices), topical corticosteroids (TCS), and topical calcineurin inhibitors (TCIs). TCS remain the cornerstone of traditional AD therapy and exert anti-inflammatory effects by binding to cytoplasmic glucocorticoid receptors. To date, ten TCS products have been approved globally for AD treatment, including hydrocortisone and mometasone furoate. TCIs, such as tacrolimus and pimecrolimus, inhibit calcineurin activity and prevent T-cell activation. Despite their standard use, topical agents are limited by suboptimal efficacy and potential adverse effects, including skin atrophy, burning, and stinging sensations. Consequently, a substantial proportion of patients with moderate-to-severe AD require systemic therapy. ▶ Small-molecule immunosuppressants: For severe AD refractory to topical therapy, systemic immunosuppressants such as cyclosporine A (CsA), methotrexate (MTX), azathioprine (AZA), and mycophenolate mofetil (MMF) may be employed. However, long-term systemic use is associated with significant adverse effects, including gastrointestinal intolerance, hepatotoxicity, nephrotoxicity, bone marrow suppression, and thrombotic events. ▶ Phototherapy: Phototherapy is considered a second-line intervention for patients who respond poorly to topical and conventional systemic treatments or who have contraindications or intolerance. According to American Academy of Dermatology (AAD) guidelines, narrowband ultraviolet B (NB-UVB) phototherapy is recommended for moderate-to-severe AD. NB-UVB induces DNA photoproducts that disrupt transcription and inhibit hyperproliferative epidermal cell division. In addition, phototherapy-induced oxidative stress suppresses antigen presentation and dendritic cell–mediated T-cell activation. Despite its efficacy, phototherapy carries limitations, including photodamage, erythema, and potential long-term risks such as melanoma and cataracts. Overall, the lack of precise targeting and the risk of adverse effects associated with conventional therapies limit their ability to meet clinical demands for “high efficacy with low toxicity.” As the central roles of Th2 inflammation, cytokine networks, and key signaling pathways in AD pathogenesis have become increasingly clear, precision targeted therapies have emerged, opening new avenues for more effective and disease-specific treatment. 02 Systemic Targeted Therapies ▶ Biologics: For patients with moderate-to-severe AD inadequately controlled by topical therapy, systemic biologic agents—primarily monoclonal antibodies—are required. The clinical success of biologics reflects decades of progress in target discovery and translational development. Since the identification of IL-4, IL-13, and other core targets in the 1990s–2000s, the immunopathology of AD has been progressively elucidated.The approval of dupilumab in 2017 marked the beginning of the biologics era in AD treatment, representing a major milestone from target discovery to clinical validation. Subsequently, antibody development has entered a phase characterized by multi-target strategies and global and domestic commercialization. While IL-4Rα and IL-13 remain mature and well-established targets, emerging targets such as OX40 have advanced into late-stage clinical development. Locally developed biologics, including spesolimab, have achieved regulatory approval after 2024. Overall, the pipeline is rapidly expanding toward broader pathway coverage and patient-specific treatment options (Figure 4). ▲ Figure 4. Development timeline of antibody therapeutics for atopic dermatitis (Phase III and beyond, December 2025) Monoclonal antibodies exert therapeutic effects by selectively targeting key immune cells and cytokines involved in AD pathogenesis, thereby blocking inflammatory signaling cascades, restoring barrier function, and alleviating pruritus. These agents demonstrate robust efficacy and favorable safety profiles, offering transformative treatment options for patients with moderate-to-severe disease. To date, five monoclonal antibodies have been approved globally for AD (Table 1): lebrikizumab and tralokinumab (anti–IL-13), nemolizumab (anti–IL-31Rα), spesolimab (anti–IL-4Rα), and dupilumab (anti–IL-4Rα). Dupilumab, the first fully human IgG4 monoclonal antibody targeting IL-4Rα, achieved global sales of EUR 13.07 billion (~USD 14.1 billion) in 2024, surpassing Humira and becoming a new benchmark therapy in the autoimmune disease field. ▼ Table 1. Approved monoclonal antibodies for atopic dermatitis worldwide (December 2025) A systematic analysis of 49 therapeutic targets currently under investigation in AD is shown in Figure 5. These include established targets such as IL-4Rα, IL-13, and IL-31Rα, as well as emerging targets including TSLP, OX40L, and OX40. ▲ Figure 5. Distribution of antibody drug targets under development for atopic dermatitis (December 2025) (1) IL-4/IL13/IL4Rα/IL13α1 IL-4 and IL-13 are central Th2 cytokines in AD pathogenesis. They share structural homology and the IL-4Rα receptor subunit and are primarily produced by activated Th2 cells, with additional contributions from type 2 innate lymphoid cells (ILC2s), mast cells, and basophils. Binding of IL-4 and IL-13 to IL-4Rα/IL-13Rα heterodimeric receptors activates downstream pathways such as JAK/STAT (Figure 6), promoting Th2 differentiation, suppressing Th1/Th17 responses, and inducing IgE production. Targeting this axis represents a cornerstone of precision therapy in AD. Agents such as dupilumab and spesolimab block IL-4Rα signaling, while IL-13–specific antibodies (tralokinumab and lebrikizumab) have also demonstrated significant clinical efficacy. (2) IL31/IL31Rα IL-31, predominantly produced by Th2 cells, is a key mediator of the itch–scratch cycle in AD. It exerts its effects by binding to IL-31Rα/OSMRβ heterodimeric receptors expressed on immune cells, keratinocytes, and peripheral sensory neurons, activating JAK/STAT and MAPK pathways (Figure 6). Nemolizumab, a monoclonal antibody targeting IL-31Rα, effectively interrupts IL-31–mediated signaling and alleviates pruritus. ▲ Figure 6. JAK–STAT signaling pathway in Th2-mediated immune responses in atopic dermatitis (3) TSLP Thymic stromal lymphopoietin (TSLP) is produced by keratinocytes in response to allergens, pathogens, or physical injury. TSLP activates dendritic cells, enhances antigen presentation, induces costimulatory molecule expression, and promotes Th2 polarization, driving type 2 inflammation dominated by IL-4 and IL-13 (Figure 7). Elevated TSLP levels in serum and lesional skin correlate positively with disease activity and severity in AD patients. Tezepelumab, an anti-TSLP monoclonal antibody, has demonstrated significant efficacy in phase II clinical trials. ▲ Figure 7. The role of TSLP in the pathogenesis of atopic dermatitis (4) OX40/OX40L OX40 and its ligand OX40L belong to the TNF superfamily. OX40 is primarily expressed on activated T cells, whereas OX40L is expressed on antigen-presenting cells, endothelial cells, and airway smooth muscle cells. Their interaction promotes T-cell activation, differentiation, and survival (Figure 8). Increased numbers of OX40-expressing effector T cells are observed in AD lesions. Anti-OX40 antibodies block OX40–OX40L signaling, reducing T-cell proliferation, survival, and memory formation, and suppressing multiple T-cell subsets, including Th1, Th2, Th17, and Th22. Several OX40/OX40L-targeting antibodies—such as rocatinlimab, telazorlimab, and amlitelimab—are under development and have demonstrated durable clinical responses even after treatment discontinuation. ▲ Figure 8. The role of OX40/OX40L in the pathogenesis of atopic dermatitis Future trends in biologic therapy for AD are expected to center on multi-target synergy, molecular innovation, and individualized, stage-based disease management. Key directions include: 1. Development of bispecific or trispecific antibodies (e.g., dual blockade of IL-4Rα and IL-31Rα) to address complex inflammatory pathways; 2. Exploration of novel targets such as IL-22 and IL-33; 3. Optimization of pharmacokinetics and delivery through long-acting formulations, antibody fusion proteins, nanobodies, and extended-interval subcutaneous or topical formulations to improve adherence; 4. Advancement of precision medicine using biomarkers or endotype-based stratification to guide therapy selection. 03 Small-Molecule Targeted Therapies Although biologics provide highly precise targeting, they are limited by injectable administration, restricted pathway coverage, and relatively high cost. Small-molecule targeted therapies, by contrast, can penetrate the skin barrier or act intracellularly to modulate multiple signaling pathways, such as JAK–STAT, and offer advantages in manufacturing cost, oral or topical administration, and patient accessibility. As such, they represent a critical complement to biologic therapies in AD. (1) Janus kinase inhibitors (JAKi) JAK inhibitors competitively bind to the ATP-binding site of JAKs, preventing phosphorylation and activation of the JAK–STAT pathway and reducing pro-inflammatory cytokine production. Currently, six JAK inhibitors have been approved for AD (Table 2): three oral agents (baricitinib, abrocitinib, and upadacitinib) for moderate-to-severe disease, and three topical agents (delgocitinib, ruxolitinib, and others) for mild-to-moderate AD. However, due to systemic bioavailability, oral JAK inhibitors carry potential safety concerns. The U.S. FDA mandates boxed warnings for all JAK inhibitors, highlighting risks of serious infections, malignancies, major adverse cardiovascular events, and thrombosis. (2) Phosphodiesterase-4 inhibitors (PDE4i) PDE4 inhibitors selectively inhibit PDE4, leading to increased intracellular cAMP levels and suppression of pro-inflammatory cytokine production. Three PDE4 inhibitors have been approved for AD (Table 2), including crisaborole, difamilast, and roflumilast. Adverse effects of topical PDE4 inhibitors are predominantly local and include burning, stinging, erythema, scaling, and dryness, which are generally mild to moderate and tend to resolve with continued use. (3) Aryl hydrocarbon receptor (AHR) modulators AHR modulators activate the AHR pathway to regulate keratinocyte differentiation and barrier repair–related gene expression, including filaggrin, thereby suppressing Th2/Th22 inflammation and improving barrier function. Tapinarof represents a key example (Table 2). However, long-term safety data remain limited and require further validation. ▼ Table 2. Approved small-molecule targeted therapies for atopic dermatitis worldwide (December 2025) 4. Summary and Outlook Atopic dermatitis is a chronic inflammatory skin disease closely linked to immune imbalance, genetic susceptibility, and environmental factors. Substantial progress in both mechanistic research and clinical management has laid a solid foundation for future advances. Current treatment strategies follow a stratified intervention framework: topical therapies dominate management of mild-to-moderate disease, while biologics and JAK inhibitors enable precise systemic control in moderate-to-severe or refractory cases. Given the strong alignment between biologic targeting strategies and the heterogeneous immunopathology of AD—as well as the potential for combination or sequential targeted therapies when single agents are insufficient—biologics are expected to dominate the AD therapeutic landscape in the coming years. Nevertheless, the complexity of AD necessitates deeper investigation. Future research should focus on three key areas: 1. Long-term, population-spanning outcome studies to assess efficacy and safety across age groups and genetic backgrounds;  2. Integrative genomic and transcriptomic analyses to construct individualized molecular profiles for personalized therapy;  3. Application of nanotechnology-based drug delivery systems to enhance skin penetration, reduce systemic toxicity, and improve bioavailability and dose control.  In conclusion, AD research has transitioned from mechanistic elucidation to precision intervention. With continued integration of multidisciplinary technologies and accumulation of evidence-based clinical data, future AD management will achieve more precise mechanistic understanding, individualized treatment strategies, and safer, more effective therapeutic outcomes—ultimately delivering greater clinical benefit to patients. ▶ Reference [1] Yosipovitch G, Kim BS, Ständer S, Elmariah SB, Prajapati VH, Kabashima K, Gallo G, Rueda MJ, Pierce E, Ding Y, Kwatra SG. Efficacy of Lebrikizumab on Pruritus: A Narrative Review. Adv Ther. 2025 Dec 3. [2] Chai H, Siu WS, Ma H, Li Y. 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