动脉粥样硬化始于血管内皮功能障碍和血管内壁胆固醇滞留，随后引发慢性炎症反应。利用他汀类药物和PCSK9抑制剂降低胆固醇是目前治疗动脉粥样硬化性心血管病患者的主要手段，但是即使胆固醇降了，炎症风险还在，就像灭火没灭透，总有余烬复燃。动脉粥样硬化不仅是胆固醇问题，更是炎症的慢性战争。内皮细胞是血管的守门员，被炎症因子（例如肿瘤坏死因子α、白细胞介素1β）一刺激，就招来免疫细胞，形成恶性循环。现有的抗炎药物太少，还有些副作用，例如白细胞介素1β抗体可能增加感染风险。老药里找新用，既能省时省力，又能降低开发风险。
2026年1月9日，美国心脏学会官方期刊《循环研究》在线发表安徽省立医院（中国科学技术大学附属第一医院）、浙江大学医学院附属第一医院、蚌埠医科大学药学院、广东省人民医院、澳大利亚格里菲斯大学生物医学与糖组学研究所、安徽医科大学公共卫生学院、中国科学技术大学内分泌与代谢病研究所、代谢健康与泛血管病安徽省重点实验室的研究报告，发现用于治疗乳腺癌的临床药物奈拉替尼可预防血管炎症和动脉粥样硬化。
该研究首先用肿瘤坏死因子α和白细胞介素1β刺激人类内皮细胞获得基因表达数据集，随后用智能筛药工具连接图谱对美国食品药品监督管理局已经批准上市药物进行海选，最后用低密度脂蛋白受体阴性小鼠模型对海选出的药物进行小鼠体内抗动脉粥样硬化作用评价。这就好比先让内皮细胞发炎，再录下基因求救信号，然后在数据库里找哪些药物能够发出镇静信号。
结果发现，已经上市8年用于治疗乳腺癌的临床药物奈拉替尼具有广泛内皮细胞抗炎作用，能够抑制由3种不同的促炎刺激物（肿瘤坏死因子α、白细胞介素1β和脂多糖）诱发的内皮细胞炎症，甚至比一些已知抗炎药更安全。
有趣的是，奈拉替尼的抗炎作用与其经典靶点HER2抑制作用无关，HER2在血管里几乎不表达，即使强行关闭HER2，抗炎效果照样在。
进一步转录组测序机制分析表明，奈拉替尼能够直接结合凋亡信号调节激酶ASK1并抑制ASK1激活。重要的是，对于低密度脂蛋白受体阴性小鼠，无论雄性还是雌性，奈拉替尼治疗都能降低斑块负荷，缩小坏死核心区域，并减轻病变部位的巨噬细胞浸润。当强行过表达ASK1时，奈拉替尼就失灵了，这反向验证了靶点的准确性，结合力堪比钥匙和锁。这说明，奈拉替尼的抗炎路径是隐藏的捷径，并不依赖癌症靶点。
临床转化发现，奈拉替尼联合标准降脂药物瑞舒伐他汀与他汀类药物单药治疗相比，抗动脉粥样硬化效果显著提高。精准蛋白质组学分析明确指出，联合治疗可减轻低密度脂蛋白受体阴性小鼠血清炎症相关细胞因子和趋化因子的水平，动脉粥样硬化斑块更少，白细胞介素、7趋化因子配体2等血清炎症因子也降得更狠，相当于降脂＋抗炎双管齐下，把动脉粥样硬化的两个根都刨了。
因此，该研究结果表明，奈拉替尼可作为治疗血管炎症和动脉粥样硬化进一步开展人类临床研究，从而将临床前发现转化为人体临床研究的努力大大简化，像在旧书堆里翻出一本武功秘籍，原本用来治疗乳腺癌的药，竟然能对付动脉粥样硬化这种慢性杀手，展现了重新定义问题的智慧：不埋头造新药，而是用数据工具翻旧账，找到奈拉替尼这条暗线，这就像创业与其从零开始，不如在现有资源里找增量。复杂疾病需要多靶点思维，动脉粥样硬化不是单一路径，抗炎与降脂并举才能破局。人工智能筛药是未来趋势，这类工具会让药物发现更高效、更便宜。乳腺癌患者或成最大获益者，奈拉替尼若用于心血管，可能让癌症患者一石二鸟，但是需要警惕腹泻等副作用。总之，该研究就像意外之书，提醒我们：答案有时藏在隔壁房间，科学的进步往往来自跨界联想。这是用旧钥匙开新锁的典范：不改变药本身，而是改变我们对疾病的理解。在医疗资源紧张的今天，这种精益创新或许比造新药更有生命力。
Circ Res. 2026 Jan 9. IF: 16.2
Neratinib, a Clinical Drug Against Breast Cancer, Protects Against Vascular Inflammation and Atherosclerosis.
Zhang FS, He C, Yin Y, Wang Z, Wu X, Kamato D, Leng R, Luo JY, Weng J, Xu S.
The First Affiliated Hospital of University of Science and Technology of China (USTC), USTC, Hefei; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Pharmacy, Bengbu Medical University, China; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Institute for Biomedicine and Glycomics, Griffith University, Nathan, QLD, Australia; School of Public Health, Anhui Medical University, Hefei, China; Institute of Endocrine and Metabolic Diseases, USTC, Hefei; Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, China.
BACKGROUND: Atherosclerosis commences with endothelial dysfunction and the retention of cholesterol within the vessel wall, followed by a chronic inflammatory response. Lowering LDL-C (low-density lipoprotein-cholesterol; such as statins and PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) is the mainstay of current treatment for patients with atherosclerotic cardiovascular diseases, but residual inflammatory risk remains high.
METHODS: To address this pressing challenge, we used connectivity map screening of Food and Drug Administration-approved drugs, using perturbational data sets obtained from TNF-α (tumor necrosis factor-α) and IL (interleukin)-1β-stimulated human endothelial cells. Male and female Ldlr-/- mouse models were used to evaluate the in vivo antiatherosclerotic effect of the hit compound identified.
RESULTS: This screening endeavor allows us to identify neratinib, a clinical drug against breast cancer, as the hit compound with broad anti-inflammatory actions in endothelial cells. Further studies reveal that neratinib inhibited endothelial cell inflammation elicited by 3 different proinflammatory stimuli (TNF-α, IL-1β, and lipopolysaccharide). Intriguingly, the anti-inflammatory effect of neratinib was independent of its classical target HER2 (human epidermal growth factor receptor 2)/ERBB2 inhibition. Further mechanistic investigation revealed that neratinib directly binds to ASK1 (apoptosis signal-regulating kinase 1) and suppresses ASK1 activation. Importantly, in both male and female Ldlr-/- mice, treatment with neratinib decreased the plaque burden, reduced the necrotic core size, and mitigated lesional macrophage infiltration. Of translational impact, we observed that neratinib, in conjunction with the use of rosuvastatin (a standard lipid-lowering drug), produced superior antiatherosclerotic effects compared with statin monotherapy. Olink proteomics study pinpointed that combination treatment alleviated inflammation-related cytokines/chemokines in the serum from Ldlr-/- mice.
CONCLUSIONS: Taken together, these findings support the concept that neratinib could be tested as a repurposed drug for vascular inflammation and atherosclerosis, thereby streamlining efforts to translate preclinical discoveries to clinical testing in humans.
KEYWORDS: MAP kinase kinase kinase 5; atherosclerosis; cardiovascular diseases; endothelial cells; foam cells
PMID: 41510568
DOI: 10.1161/CIRCRESAHA.125.326508