Survodutide

GLP-1受体激动剂（GLP-1RA）是过去二十年代谢疾病领域最具革命性的药物类别之一。从2005年首款产品艾塞那肽获批至今，GLP-1R相关研发管线已近800条。在如此程度的竞争下，GLP-1R相关代谢药物的研发思路已从“单靶点长效化”进入几个新阶段：口服便携化——旨在提高依从性、降低成本、避免注射多靶点协同——旨在追求更强减重与代谢获益适应症拓展——旨在突破糖尿病/肥胖标签，竞争其他赛道在上述新方向的研发中，动物模型的要求也在不断提高。从单一靶点到多靶点人源化代谢疾病模型，从传统药效终点到多组学动态监测，如何构建与新一代GLP-1R药物研发需求相匹配的精准动物模型，已成为赛道突围中不可回避的核心技术命题。口服药物研发需更精准动物模型支撑口服便携化是GLP-1R药物研发中技术门槛较高的方向之一。与注射剂不同，口服GLP-1RA面临多肽药物的胃肠道降解、黏膜屏障穿透力低、生物利用度差等多重挑战。目前，口服GLP-1药物的研发主要以两种方式进行：口服多肽制剂和口服小分子非肽类制剂。口服多肽制剂方面，目前诺和诺德的司美格鲁肽口服片已全球获批上市，它通过了吸收增强剂SNAC技术，在胃内局部升高pH值、保护司美格鲁肽不被胃蛋白酶降解，同时促进药物跨胃黏膜上皮细胞吸收。口服小分子非肽类制剂方面，研发思路是利用小分子GLP-1RA的分子量远小于多肽的优势，设计为高生物利用度的口服制剂。然而，小分子激动剂往往对人GLP-1R具有高度种属选择性，在野生型啮齿动物中可能完全不激活受体。这一特写对动物模型均提出了更为严苛的要求。南模生物的hGLP1R人源化小鼠可有效支撑小分子口服GLP-1RA的体内活性验证与药效评价，是口服便携化方向研发不可或缺的核心工具。hGLP1R小鼠（NM-HU-200220）验证数据Fig. 1 The efficacy of orforglipron in hGLP1R mice. The hGLP1R mice were fed CD or HFD. Administer saline or oroglipron orally once daily until euthanasia. Semaglutide was administered subcutaneously once daily until euthanasia.多靶点协同思路中动物模型的关键支撑多靶点GLP-1药物已成为代谢疾病治疗领域的核心发展方向，目前与 GLP-1R 协同开发的“多靶点”策略，集中在几条生理轴：肠促胰素轴：GIPR、GCGR等食欲/饱腹感轴：Amylin、PYY/NPY2、GDF15/GFRAL、MC4R等代谢/肝脏轴：FGF21等体成分/肌肉轴：Activin/Myostatin 通路图. 在临床前研究中新一代GLP-1R相关靶点的主要作用。[1]从靶点组合来看，目前较为热门的有以下几种组合： GLP-1R / GIPR GLP-1R/GIPR双靶点激动剂是目前多靶点策略中临床验证最为充分的方向。GIPR是葡萄糖依赖性促胰岛素多肽受体，其配体GIP由肠道K细胞分泌，主要作用是促胰岛素分泌，但在脂肪组织和骨代谢中也有作用。GIP与GLP-1同属肠促胰素家族，两者在血糖调控和能量代谢中发挥互补作用。目前该赛道已有礼来的替尔泊肽（Tirzepatide）获批上市，恒瑞医药的RS-9531申请上市，博瑞医药的BGM0504完成III期，众生睿创的RAY1225在II期取得24周减重21.18%的积极数据等。 GLP-1R / GCGR GLP-1R与GCGR协同激活，是多靶点策略中另一条已获临床验证的重要方向。GCGR是胰高血糖素受体，其内源性配体GCG由胰岛α细胞分泌，其主要作用为在机体血糖较低时通过促进肝糖原分解和糖异生来升高血糖。近年研究发现，外源性GCG可减少肝脏甘油三酯合成、促进肝脏脂解，增加产热提高全身能量消耗。GLP-1与GCG的连用形成了一种互补机制：GLP-1R激动促进降糖、抑制食欲和延缓胃排空，GCGR激动促进糖原与脂肪分解。目前该赛道已有多款分子进入临床后期。信达生物的玛仕度肽（Mazdutide）获批上市，勃林格殷格翰的Survodutide在II期试验中46周平均减重18.7%；阿斯利康的Cotadutide（MEDI0382）在临床前验证了减重与肝脏获益。国内四环医药旗下惠升生物的P052注射液已获批IND，临床前数据效果优于司美格鲁肽。 GLP-1R / GIPR / GCGR GLP-1R/GIPR/GCGR三靶组合中，前两者负责抑制食欲、延缓胃排空、促胰岛素分泌、平稳控制血糖，GCGR则提升基础代谢、加速内脏脂肪分解、降低甘油三酯与炎症水平。目前该赛道中，礼来的Retratrutide已进入III期临床，48周平均减重24.2%。国内方面，联邦制药与诺和诺德联合开发的UBT251已完成中国II期临床。翰宇药业的HY3003已完成临床前研究。歌礼的ASC3于2025年11月启动临床开发。恒瑞医药HRS-4729于2026年8月获国家药监局临床试验批准。 GLP-1R / FGF21 及更高阶组合 FGF21 主要由肝脏分泌，可改善胰岛素敏感性、减少肝脂肪、改善脂代谢。引入FGF21靶点的核心目的是直接靶向肝脏代谢与纤维化。目前常见的研发管线有GLP-1R / FGF21R 双靶点激动剂（如东阳光的HEC88473，质肽生物的ZT003）、GLP-1R/GCGR/FGF21R（如华东医药旗下道尔生物的DR10624）、GLP-1R/GIPR/FGF21R三靶点激动剂（如上海民为生物的MWN105）等。上述药物的临床前验证均高度依赖动物模型。南模生物自主研发的hGCGR/hGLP1R、hGLP1R / hGIPR双靶点、hGLP1R /hGIPR / hGCGR、hFGFR1/hGIPR/hGLP1R等多靶点人源化小鼠，在基因层面精准模拟了药物在人体的作用靶点，是加速该类双靶点药物临床转化落地的关键工具。hGCGR/hGLP1R小鼠（NM-HU-233747）验证数据Fig. 1 Body weight change of HFD-induced hGCGR/hGLP1R obese mice treated with Cotadutide.The hGCGR/hGLP1R mice were fed CD or HFD. PBS or Cotadutide was administered subcutaneously once daily until euthanasia. (A) Body weight, (B) body weight change and (C) Food intake per mouse were recorded (n=6, Mean ± SEM, ***p<0.001, Group2 vs. Group3).Abbr: CD, chow diet. HFD, high-fat diet.Fig. 2 Fat mass and lean mass changes of HFD-induced hGCGR/hGLP1R obese mice treated with Cotadutide.The hGCGR/hGLP1R mice were fed CD or HFD. PBS or Cotadutide was administered subcutaneously once daily until euthanasia. At the study endpoint, fat and lean mass were determined. (n=6, Mean ± SEM, *p<0.05, ***p<0.001).Abbr: CD, chow diet. HFD, high-fat diet.Fig. 3 Liver triglyceride, cholesterol content and blood glucose levels of HFD-induced hGCGR/hGLP1R obese mice treated with Cotadutide.The hGCGR/hGLP1R mice were fed CD or HFD. PBS or Cotadutide was administered subcutaneously once daily until euthanasia. (n=6, Mean ± SEM, *p<0.05, **p<0.01).Abbr: CD, chow diet. HFD, high-fat diet.Fig. 4 Adipose tissue weight of HFD-induced hGCGR/hGLP1R obese mice treated with Cotadutide.The hGCGR/hGLP1R mice were fed CD or HFD. PBS or Cotadutide was administered subcutaneously once daily until euthanasia.(n=6, Mean ± SEM, **p<0.01, ***p<0.001).Abbr: CD, chow diet. HFD, high-fat diet.Fig. 5 Oxygen consumption, carbon dioxide production, respiratory exchange ratio and heat production of HFD-induced hGCGR/hGLP1R obese mice treated with Cotadutide.The hGCGR/hGLP1R mice were fed CD or HFD. PBS or Cotadutide was administered subcutaneously once daily until euthanasia. Mice were housed in individual metabolic cages. (n=6, Mean ± SEM, ***p<0.001).Abbr: CD, chow diet. HFD, high-fat diet.上下滑动查看hGLP1R/hGIPR/hGCGR小鼠（NM-XA-240884）验证数据Fig. 1 The efficacy of retatrutide in of HFD-induced hGLP1R/hGIPR/hGCGR mice. The hGLP1R mice were fed CD or HFD. The hGLP1R/hGIPR/hGCGR mice were fed CD or HFD. Saline or retatrutide was administered subcutaneously once daily until euthanasia.GLP1R相关人源化小鼠除上述介绍外，南模生物还可以提供多种围绕GLP1R靶点的人源化小鼠，匹配新一代GLP-1R药物研发需求。表1. GLP1R相关人源化小鼠参考文献：[1] Kusminski C, Perez-Tilve D, Müller T, Transforming obesity: The advancement of multi-receptor drugs Cell, 187, 3829-3853

Nature Medicine Volume 32 Issue 7 自然医学 32卷 7期 https://www.nature.com/nm/volumes/32/issues/7 Editorial（社论） 1 Oncology must confront hidden side effects 肿瘤学必须正视隐匿不良反应 Nature Medicine volume 32（7）, page 2321 News（新闻） 2 Taming the inflamed heart 调控炎症性心脏病变 Charlotte Harrison Nature Medicine volume 32（7）, pages 2322-2323 News Feature（新闻专题） 3 When the real world becomes the trial 当现实世界成为临床试验场域 Marianne Guenot Nature Medicine volume 32（7）, pages 2324–2327 Correspondence（读者来信） 4 What Galen’s dissections reveal about tacit learning in modern medical education 盖伦解剖研究对现代医学教育中默会学习的启示 Andres PelavskiGabriele TorcolettiOrly Lewis Nature Medicine volume 32（7）, pages 2328–2329 5 What Utah’s clinical AI sandbox reveals about independent oversight 犹他州临床人工智能沙箱对独立监管机制的启示 Rahul GorijavoluNikhil JaiswalLeo Anthony Celi Nature Medicine volume 32（7）, pages 2330–2332 6 A case of artificial intelligence-enhanced diagnostics leading to heart transplantation 人工智能辅助诊断促成心脏移植一例 Heidi S. HartmanJoshua FinerPierre Elias Nature Medicine volume 32（7）, pages 2333–2334 7 Unintended consequences of legacy oversight in digital medicine 数字医学领域传统监管模式带来的非预期后果 Jochen K. LennerzDaniela AllendeAnne M. Stowman Nature Medicine volume 32（7）, pages 2335–2337 8 Incretin therapies, nutrition and food insecurity in the UK 英国肠促胰素治疗、营养状况与粮食不安全问题 Marie SpreckleyCara F. RuggieroAdrian Brown Nature Medicine volume 32（7）, pages 2338–2339 World View（全球观点） 9 Manageable toxicity is not a label — it is an oxymoron 可控制毒性并非标签，而是矛盾表述 From the patient’s perspective, toxicity is manageable only when it is met with empathy. 从患者视角而言，只有饱含人文关怀，不良反应才谈得上可控。 Laura Book Nature Medicine volume 32（7）, page 2340 10 Downplaying toxicities in cancer drug trials is not acceptable 肿瘤药物临床试验中淡化不良反应不可取 Bishal Gyawali Nature Medicine volume 32（7）, page 2341  Comment（述评） 11 Wearables as personal health custodians 可穿戴设备：个人健康守护者 Lei LuJosip Car Nature Medicine volume 32（7）, pages 2342–2345 12 Australia legislates against genetic discrimination in life insurance 澳大利亚立法禁止人寿保险领域的基因歧视 Jane Tiller Nature Medicine volume 32（7）, pages 2346–2348 13 A roadmap to competitive preclinical packages 具备竞争力的临床前研究方案构建路线图 Mustafa KhasrawMegan C. BenzJose R. Conejo-Garcia Nature Medicine volume 32（7）, pages 2349–2352 14 Brain Health for Economic Resilience: a data-driven framework for the brain-positive economic transition 保障大脑健康助力经济韧性：推动益脑经济转型的数据驱动框架 Harris A. EyreRym AyadiSimon Fischer-Baum Nature Medicine volume 32（7）, pages 2353–2355 News & Views（新闻与观点） 15 Long-term health risks of e-cigarettes after smoking cessation 戒烟后使用电子烟的长期健康风险 Mahdi SheikhPamela M. Ling Nature Medicine volume 32（7）, pages 2356–2357 16 CAR T cells take on precancers CAR-T细胞靶向癌前病变 Eric M. JurgensSham Mailankody Nature Medicine volume 32（7）, pages 2358–2359 17 Lassa fever countermeasures gather pace 拉沙热防控举措加速推进 Daniel Jenkin Nature Medicine volume 32（7）, pages 2360–2361 18 Shifting the goalposts in obesity drug development 肥胖药物研发目标的重新界定 W. Timothy Garvey Nature Medicine volume 32（7）, pages  pages 2362–2363 Research Briefings（研究简报） 19 General-purpose chatbots outperform clinical AI tools on physicians’ real-world questions 通用对话机器人在医师现实临床问题上表现优于专用临床人工智能工具 Nature Medicine volume 32（7）, pages 2364–2365 20 An AI framework for multi-disease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Nature Medicine volume 32（7）, pages 2366–2367 Perspectives（前瞻观点） 21 Immune aging biomarkers for clinical trials 适用于临床试验的免疫衰老生物标志物 Andrea CiprianoJamie JusticeChiara M. S. Herzog Nature Medicine volume 32（7）, pages 2368–2382 Review Articles（综述） 22 Biological aging clocks in health and disease 健康与疾病状态下的生物学衰老时钟 Tony Wyss-CorayEric J. Topol Nature Medicine volume 32（7）, pages 2383–2394 Matters Arising（学术争鸣） 23 Limited evidence of AI superiority in seasonal influenza vaccine strain selection 尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势 Simon P. J. de JongColin A. Russell Nature Medicine volume 32（7）, pages 2395–2397 24 Reply to: Limited evidence of AI superiority in seasonal influenza vaccine strain selection 对《尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势》一文的回应 Wenxian ShiJeremy WohlwendRegina Barzilay Nature Medicine volume 32（7）, pages 2398–2400 Brief Communications（简讯） 25 Spatiotemporal diffusion of the 2024 Oropouche outbreak in Cuba 2024年古巴奥罗普切热暴发的时空传播特征 Rosario GravierMelissa M. PerezMaria G. Guzman Nature Medicine volume 32（7）, pages 2401–2404 26 General-purpose large language models outperform specialized clinical AI tools on medical benchmarks 通用大语言模型在医学基准测试中优于专用临床人工智能工具 Krithik VishwanathAnton AlyakinEric Karl Oermann Nature Medicine volume 32（7）, pages 2405–2409 Articles（论著） 27 Electronic cigarette use after smoking cessation and lung cancer risk 戒烟后使用电子烟与肺癌风险 Yeon Wook KimEung Joo ParkChoon-Taek Lee Nature Medicine volume 32（7）, pages 2410–2419 28 Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial Ciltacabtagene autoleucel治疗高危冒烟型（无症状）多发性骨髓瘤：CAR-PRISMⅡ期临床试验 Omar NadeemDavid M. Cordas dos SantosIrene M. Ghobrial Nature Medicine volume 32（7）, pages 2420–2429 29 Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial Cibisatamab联合FAP-4-1BBL治疗微卫星稳定型结直肠癌：Ⅰb期临床试验 Ignacio MeleroTamara TanosVictor Moreno Nature Medicine volume 32（7）, pages 2430–2439 30 Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, pages 2440–2448 31 Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial 抗LAG-3单抗联合或不联合抗PD-1单抗治疗复发性胶质母细胞瘤：Ⅰ期临床试验 Michael LimXiaobu YeStuart A. Grossman Nature Medicine volume 32（7）, pages 2449–2460 32 Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2− breast cancer: a randomized phase 2 trial 立体定向体部放疗联合度伐利尤单抗与奥来鲁单抗新辅助治疗ER阳性HER2阴性乳腺癌：随机Ⅱ期临床试验 Alex De CaluwéIsabelle DesmoulinsLaurence Buisseret Nature Medicine volume 32（7）, pages 2461–2472 33 Post-adjuvant chemotherapy in ctDNA-positive patients with resected colorectal cancer: a randomized phase 3 trial ctDNA阳性结直肠癌术后辅助化疗：随机Ⅲ期临床试验 Hideaki BandoJun WatanabeTakeshi Kato Nature Medicine volume 32（7）, pages 2473–2480 34 Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial 多抗原靶向T细胞治疗儿童中枢神经系统肿瘤：Ⅰ期临床试验 Stephanie GomezRachel A. DiCioccioEugene I. Hwang Nature Medicine volume 32（7）, pages 2481–2493 35 AI framework for multidisease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Xiayin ZhangQinyi LiHonghua Yu Nature Medicine volume 32（7）, pages 2494–2503 36 Long-term independent use of an intracortical brain–computer interface for speech and cursor control 皮层内脑机接口用于语音与光标控制的长期独立应用研究 Nicholas S. CardTyler Singer-ClarkDavid M. Brandman Nature Medicine volume 32（7）, pages 2504–2510 37 Adjuvanted inactivated rabies virus-vectored Lassa virus vaccine in healthy adults: a phase 1 trial 含佐剂灭活狂犬病毒载体拉沙病毒疫苗在健康成人中的Ⅰ期临床试验 Justin R. OrtizDrishya KurupMatthias J. Schnell Nature Medicine volume 32（7）, pages 2511–2521 38 Favipiravir for Lassa fever: an open-label, randomized controlled phase 2 trial 法匹拉韦治疗拉沙热：开放标签随机对照Ⅱ期临床试验 Cyril EramehKevin OkwaraekeMirjam Groger Nature Medicine volume 32（7）, pages 2522–2532 39 Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial 双特异性广谱中和抗体10E8.4/iMab在HIV-1感染者与健康人群中的部分随机Ⅰ期临床试验 Deborah A. TheodoreBryan T. MayerMagdalena E. Sobieszczyk Nature Medicine volume 32（7）, pages 2533–2545 40 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial 15菌株活体生物制剂与同源供体粪菌移植治疗复发性艰难梭菌感染：随机Ⅰb期临床试验 Lukas BethlehemLorenza BartuAri Grinspan Nature Medicine volume 32（7）, pages 2546–2555 41 Innate immune responsiveness predicts enhanced cellular immunity and symptomatic disease after controlled human influenza infection 固有免疫应答水平可预测人工流感感染后细胞免疫增强与临床发病情况 Loukas PapargyrisJiayun XuChristopher Chiu Nature Medicine volume 32（7）, pages 2556–2569 42 Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial 多巴胺激动剂普拉克索治疗快感缺失型抑郁症的疗效与靶点作用验证：随机安慰剂对照试验 Filip VentorpMarie AspDaniel Lindqvist Nature Medicine volume 32（7）, pages 2570–2578 43 Spinal cord stimulation for upper limb motor function in people with chronic post-stroke hemiparesis: a feasibility trial 脊髓电刺激改善慢性卒中后偏瘫患者上肢运动功能：可行性临床试验 Roberto M. de FreitasShovan BhatiaMarco Capogrosso Nature Medicine volume 32（7）, pages 2579–2590 44 A neuroprosthesis for restoring hand movement and sensation in a person with complete tetraplegia 神经假体用于重建完全四肢瘫痪患者手部运动与感觉功能 Santosh ChandrasekaranSarah K. WandeltChad E. Bouton Nature Medicine volume 32（7）, pages  pages2591–2601 45 Dual-target gene therapy in Parkinson’s disease: a multicenter phase 1 trial 双靶点基因疗法治疗帕金森病：多中心Ⅰ期临床试验 Mengyue NiuJifeng GuoJun Liu Nature Medicine volume 32（7）, pages 2602–2609 46 Abatacept versus hydroxychloroquine for prevention of rheumatoid arthritis in individuals with palindromic rheumatism: a randomized open-label trial 阿巴西普对比羟氯喹预防复发性风湿症进展为类风湿关节炎：随机开放标签试验 Raimon SanmartiCarolina Pérez-GarcíaIsabel Haro Nature Medicine volume 32（7）, pages 2610–2618 47 Oligonucleotide–siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial 寡核苷酸-siRNA偶联药物治疗SOD1相关肌萎缩侧索硬化：Ⅰ期临床试验 Weiqi ChenLingling JiangYilong Wang Nature Medicine volume 32（7）, pages 2619–2628 48 Multinational validation of the PREVENT and SCORE2心血管风险方程 across 6.4 million individuals 基于640万人群的多国验证：PREVENT与SCORE2心血管风险预测方程 Brendon L. NeuenRupert W. MajorVilmantas Giedraitis Nature Medicine volume 32（7）, pages 2629–2638 49 Cliramitug for depletion of cardiac amyloid transthyretin: long-term follow-up of the NI006-101 trial Cliramitug清除心脏转甲状腺素蛋白淀粉样物质：NI006-101试验长期随访结果 Peter C. KahrFabian aus dem SiepenPeter van der Meer Nature Medicine volume 32（7）, pages 2639–2646 50 Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial 小剂量地高辛治疗射血分数降低或轻度降低心力衰竭：随机对照试验 D. J. van VeldhuisenM. RienstraP. van der Meer Nature Medicine volume 32（7）, pages 2647–2653 51 The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial 微小RNA抑制剂CDR132L治疗心肌梗死后左室射血分数降低患者：随机Ⅱ期临床试验 Johann BauersachsScott D. SolomonThomas Thum Nature Medicine volume 32（7）, pages 2654–2661 52 Semaglutide versus placebo in individuals with poor weight loss after bariatric surgery: a double-blinded, randomized, placebo-controlled trial 司美格鲁肽对比安慰剂治疗减重手术术后减重不佳人群：双盲随机安慰剂对照试验 Chloe StanleyRitwika MallikJanine Makaronidis Nature Medicine volume 32（7）, pages 2662–2672 53 Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial Apitegromab用于替尔泊肽减重过程中维持瘦体重：随机双盲安慰剂对照Ⅱ期临床试验 Richard E. PratleyDouglas Scott DenhamJing L. Marantz Nature Medicine volume 32（7）, pages 2673–2678 54 Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial Orforglipron用于维持减重效果：双盲随机Ⅲb期ATTAIN-MAINTAIN试验 Louis J. AronneDeborah B. HornNeena Xavier Nature Medicine volume 32（7）, pages 2679–2687 Amendments & Corrections（勘误与更正） 55 Author Correction: Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 作者更正：基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, page 2688 56 Author Correction: Digital AVATAR therapy for distressing voices in psychosis: the phase 2/3 AVATAR2 trial 作者更正：数字虚拟化身疗法治疗精神病幻听症状：Ⅱ/Ⅲ期AVATAR2临床试验 Philippa A. GaretyClementine J. EdwardsThomas Ward Nature Medicine volume 32（7）, page 2689 57 Author Correction: Global burden of amphetamine, cannabis, cocaine and opioid use in 204 countries, 1990–2023: a Global Burden of Disease Study 作者更正：1990–2023年204个国家苯丙胺、大麻、可卡因与阿片类物质使用的全球疾病负担研究 Jiseung KangHyeon Jin KimDong Keon Yon Nature Medicine volume 32（7）, page 2690 58 Retraction Note: Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial 撤稿声明：时辰免疫化疗治疗非小细胞肺癌：随机Ⅲ期临床试验 Zhe HuangLiang ZengYongchang Zhang Nature Medicine volume 32（7）, page 2691 Nature Medicine Volume 32 Issue 8 自然医学 32卷 8期 https://www.nature.com/nm/volumes/32/issues/8 Editorial（社论） 1 Anti‑aging interventions need less hype and more clinical evidence 抗衰老干预：少一些炒作，多一些临床证据 Editorial Nature Medicine volume 32（8）, page 2693 News（新闻） 2 A turning point for gene editing in severe blood disorders 基因编辑治疗重症血液疾病迎来转折点 Carrie Arnold Nature Medicine volume 32（8）, pages 2694-2696 News Feature（新闻特写） 3 Sleep as therapy 睡眠疗法 Carrie Arnold Nature Medicine volume 32（8）, pages 2697–2700 Correspondence（通信） 4 Genetic–exposome interactions and aging clocks in dementia: the ReDLat2 initiative 遗传‑暴露组相互作用与痴呆衰老时钟：ReDLat2研究计划 Agustin IbáñezJennifer S. YokoyamaBruce L. Miller Nature Medicine volume 32（8）, pages 2701–2703 5 Bundibugyo Ebola without vaccines or therapeutics: why public health fundamentals matter more than border closures 无疫苗与治疗药物情况下的本迪布焦埃博拉疫情：公共卫生基础措施比边境封锁更为重要 Ngashi NgongoMosoka Papa FallahJean Kaseya Nature Medicine volume 32（8）, pages 2704–2705 6 Fertilizer scarcity as a failure of global health governance 肥料短缺：全球卫生治理的一项失败 Alaha NasariAmina NasariJessica Fanzo Nature Medicine volume 32（8）, pages 2706–2707 7 Mapping the human chemical exposome for public health 面向公共卫生的人类化学暴露组图谱绘制 Arthur DavidSarah LennonMichel Samson Nature Medicine volume 32（8）, pages 2708–2710 World View（全球视野） 8 When caution becomes harm 当谨慎变为伤害 Simone N. Vigod Nature Medicine volume 32（8）, page 2711 Comment（述评） 9 Enabling secure discovery in trusted research environments with improved tooling 依托优化工具在可信研究环境中实现安全数据挖掘 Vincent J. StraubMelinda C. Mills Nature Medicine volume 32（8）, pages 2712–2715 10 Reinventing biotech systems for patient impact 重塑生物技术体系，惠及患者 Kushal T. KadakiaYashodhara DashAnaeze C. Offodile II Nature Medicine volume 32（8）, pages 2716–2719 11 Why large‑scale randomized trials of live‑attenuated shingles vaccination for dementia prevention are urgently needed 亟需开展减毒活带状疱疹疫苗预防痴呆的大规模随机对照试验 Pascal Geldsetzer Nature Medicine volume 32（8）, pages 2720–2723 12 Inspiring, shaping and sustaining an African research & development agenda 推动、构建并维系非洲研发议程 Mosoka P. FallahMisaki WayengeraJean Kaseya Nature Medicine volume 32（8）, pages 2724–2726 13 Data rights are the missing pillar for modernizing consent in medicine 数据权利：医学知情同意现代化的缺失支柱 Nada S. Salem Nature Medicine volume 32（8）, pages 2727–2728 Q&A（问答） 14 Reinventing health communication for the digital era 数字时代下重塑健康传播 Natalie Healey Collection: Nature Medicine Commission on Quality Health Information for All Nature Medicine volume 32（8）, pages 2729–2731 News & Views（新闻与观点） 15 Adaptive brain stimulation 2.0 for Parkinsonian gait 用于帕金森病步态障碍的第二代自适应脑刺激 Arjun BalachandarAlfonso Fasano Nature Medicine volume 32（8）, pages 2732–2734  16 A second chance for gene therapy to restore natural hearing 基因治疗重获契机，助力恢复天然听力 Nicola Strenzke Nature Medicine volume 32（8）, pages 2735–2737 17 From RAS inhibitor resistance to rational combination strategies 从RAS抑制剂耐药到合理联合治疗策略 Paula LynchTeresa MacarullaGrainne M. O’Kane Collection: Cancer at Nature Portfolio Nature Medicine volume 32（8）, pages 2738–2740  18 Deciphering the role of histidine in cancer 解析组氨酸在肿瘤中的作用 Feyza CansizAmanda N. PopeAlpaslan Tasdogan Nature Medicine volume 32（8）, pages 2741–2742 Research Briefings（研究简报） 19 Learning from routine health system data builds better neuroimaging AI models 基于常规卫生系统数据训练构建更优神经影像人工智能模型 Research Briefing Nature Medicine volume 32（8）, pages 2743–2744 20 Early detection of Alzheimer’s disease with circular RNA from blood 基于血液环状RNA实现阿尔茨海默病早期检测 Nature Medicine volume 32（8）, pages 2745–2746 21 Non‑invasive tests for the evaluation of liver fibrosis in MASLD 代谢相关脂肪性肝病肝纤维化的无创评估检测 Nature Medicine volume 32（8）, pages 2747–2748 22 Multi‑omics maps human–pig interactions in extracorporeal liver cross‑circulation 多组学解析体外肝交叉循环中人‑猪相互作用 Nature Medicine volume 32（8）, pages 2749–2750 23 Biological aging might help to explain the rising risk of early‑onset cancer 生物衰老或可解释早发性肿瘤风险升高现象 Nature Medicine volume 32（8）, pages 2751–2752 24 Delivering the benefits of genomic data reanalysis for diagnosis equitably and at scale 公平、规模化发挥基因组数据再分析的诊断价值 Nature Medicine volume 32（8）, pages 2753–2754 25 Why high scores do not mean application readiness for health AI 为何高分不等于健康人工智能具备实际应用就绪度 Nature Medicine volume 32（8）, pages 2755–2756 Perspectives（观点） 26 Type 2 diabetes prevention across the life course 全生命周期的2型糖尿病预防 Yiying WangJennifer L. SargentAndreas L. Birkenfeld Nature Medicine volume 32（8）, pages 2757–2773 27 The next generation of antibody–drug conjugates 新一代抗体‑药物偶联物 F. MoseleA. PeltierF. André Collection: Cancer at Nature Portfolio Nature Medicine volume 32（8）, pages 2774–2785 Brief Communications（简讯） 28 Clinical profile and genomic characterization of the 2026 Bundibugyo virus index case in Uganda 乌干达2026年本迪布焦病毒首发病例的临床特征与基因组分析 Andrew NsawotebbaIsaac SsewanyanaDiana Atwine Nature Medicine volume 32（8）, pages 2786–2789 Articles（论著） 29 Immersive virtual reality with synchronous neurostimulation for upper‑limb recovery after stroke: a randomized feasibility trial 沉浸式虚拟现实联合同步神经刺激用于脑卒中后上肢功能恢复：一项随机可行性试验 Giuseppe Valerio AurucciOlivera DjordjevicStanisa Raspopovic Nature Medicine volume 32（8）, pages 2790–2802 30 Adaptive deep brain stimulation for dynamic gait control in Parkinson’s disease: a randomized feasibility trial 自适应深部脑刺激用于帕金森病动态步态调控：一项随机可行性试验 Kenneth H. LouieJannine P. BalakidDoris D. Wang Nature Medicine volume 32（8）, pages 2803–2814 31 Activity‑dependent adaptive deep brain stimulation improves gait in Parkinson’s disease 活动依赖性自适应深部脑刺激改善帕金森病患者步态 Stefano ScafaValeria de SetaEduardo M. Moraud Nature Medicine volume 32（8）, pages 2815–2830 32 Health system learning enables generalist neuroimaging models 基于卫生系统数据学习构建通用型神经影像模型 Akhil KondepudiAkshay RaoTodd Hollon Nature Medicine volume 32（8）, pages 2831–2837 33 Individualized antisense oligonucleotides for SCN2A‑related developmental epileptic encephalopathy 针对SCN2A相关发育性癫痫性脑病的个体化反义寡核苷酸治疗 Olivia Kim‑McManusLaurence MignonElizabeth Berry‑Kravis Nature Medicine volume 32（8）, pages 2838–2845 34 Re‑administration of AAV‑mediated gene therapy for OTOF‑related deafness: a single‑arm trial OTOF相关耳聋腺相关病毒介导基因治疗的再次给药：一项单臂临床试验 Xintai FanLonglong ZhangYilai Shu Nature Medicine volume 32（8）, pages 2846–2856 35 Blood‑based circular RNAs for early diagnosis of Alzheimer’s disease 基于血液环状RNA的阿尔茨海默病早期诊断 Bridget PhillipsJessie SanfordCarlos Cruchaga Nature Medicine volume 32（8）, pages 2857–2864 36 Acquired resistance to the RAS(ON) multi‑selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer RAS(ON)高选择性抑制剂daraxonrasib获得性耐药指导胰腺癌合理联合治疗策略 Ida AronchikSumit KarMallika Singh Collection: Cancer at Nature Portfolio Nature Medicine volume 32（8）, pages 2865–2877 37 MAGE‑A4/MAGE‑A8‑targeted TCR‑based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial 靶向MAGE‑A4/MAGE‑A8的TCR双特异性T细胞衔接分子治疗复发/难治性实体瘤：Ⅰ期临床试验 Martin WermkeSebastian OchsenreitherCarsten Reinhardt Nature Medicine volume 32（8）, pages 2878–2887 38 Savolitinib in MET‑amplified gastric or gastroesophageal junction adenocarcinoma: a phase 2 trial 赛沃替尼治疗MET扩增胃癌或胃食管结合部腺癌：Ⅱ期临床试验 Zhi PengTianshu LiuZhongxian Zheng Nature Medicine volume 32（8）, pages 2888–2897  39 SEZ6‑targeting antibody−drug conjugate ABBV‑706 in advanced small cell lung cancer and solid tumors: a phase 1 trial 靶向SEZ6抗体‑药物偶联物ABBV‑706治疗晚期小细胞肺癌及其他实体瘤：Ⅰ期临床试验 Lauren Averett ByersByoung Chul ChoSreenivasa Chandana Nature Medicine volume 32（8）, pages 2898–2908 40 FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial FcRH5×CD3双特异性抗体ce vostamab治疗复发难治多发性骨髓瘤：Ⅰ期临床试验 Adam D. CohenJoshua RichterAmrita Krishnan Nature Medicine volume 32（8）, pages 2909–2917 41 Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling 基于血浆谱分析筛选肿瘤免疫治疗疗效的代谢决定因素 Déborah SuissaMarine FidelleLaurence Zitvogel Nature Medicine volume 32（8）, pages 2918–2932 42 Polypill for heart failure with reduced ejection fraction: the POLY‑HF randomized trial 射血分数降低心力衰竭复方制剂：POLY‑HF随机临床试验 Ambarish PandeyNeil KeshvaniThomas J. Wang Nature Medicine volume 32（8）, pages 2933–2940 43 Oral small molecule GLP‑1 receptor agonist aleniglipron in people with overweight or obesity: a randomized, double‑blind, placebo‑controlled phase 2b trial 口服小分子GLP‑1受体激动剂aleniglipron治疗超重/肥胖人群：随机双盲安慰剂对照Ⅱb期临床试验 Julio RosenstockIldiko LingvayBlai Coll Nature Medicine volume 32（8）, pages 2941–2947 44 Survodutide in adults with obesity and metabolic dysfunction‑associated steatotic liver disease: SYNCHRONIZE‑MASLD, a randomized, double‑blind, placebo‑controlled phase 3 trial Survodutide治疗合并代谢相关脂肪性肝病的肥胖成人：SYNCHRONIZE‑MASLD随机双盲安慰剂对照Ⅲ期临床试验 Lee M. KaplanElena StartsevaPaul Hellstern Nature Medicine volume 32（8）, pages 2948–2958 45 Prospective validation of imaging and serum diagnostic biomarkers of steatohepatitis and fibrosis in MASLD: the LITMUS Imaging Study 代谢相关脂肪性肝炎及肝纤维化影像与血清诊断生物标志物的前瞻性验证：LITMUS影像研究 Michael PavlidesYasaman ValiQuentin M. Anstee Nature Medicine volume 32（8）, pages 2959–2969 46 Longitudinal multiomics profiling of extracorporeal cross‑circulation with pig liver xenografts in human decedents 人逝者猪肝异种移植体外交叉循环的纵向多组学分析 Qian GuoChan WangBrendan J. Keating Nature Medicine volume 32（8）, pages 2970–2982 47 Biological aging and generational shifts in early‑onset cancer risk 生物衰老与早发性肿瘤风险的代际变迁 Ruiyi TianXiaoyu ZongYin Cao Nature Medicine volume 32（8）, pages 2983–2990 48 Automated reanalysis of genomic data for rare disease diagnostics at scale 面向大规模罕见病诊断的基因组数据自动化再分析 Matthew J. WellandK. D. AhlquistZornitza Stark Nature Medicine volume 32（8）, pages 2991–2999 49 Divergent impacts of explainable AI for dermatological diagnosis on clinicians versus lay people 可解释人工智能皮肤病诊断对临床医师与普通人群的差异化影响 Xuhai ‘Orson’ XuHaoyu HuMarzyeh Ghassemi Nature Medicine volume 32（8）, pages 3000–3009 50 Generalizable AI predicts immunotherapy outcomes across cancers and treatments 泛化人工智能跨肿瘤类型与治疗方案预测免疫治疗疗效 Wanxiang ShenIntae MoonMarinka Zitnik Nature Medicine volume 32（8）, pages 3010–3022 51 Evaluating the robustness and readiness of large frontier models in health AI applications 健康人工智能应用中大前沿模型的稳健性与就绪度评估 Yu GuJingjing FuPaul Vozila Nature Medicine volume 32（8）, pages 3023–3031 52 Generative AI‑enabled clinical decision support system in primary care: a pragmatic, cluster‑randomized trial 基层医疗机构生成式人工智能临床决策支持系统：一项实用整群随机试验 Ambrose AgweyuPaul MwanikiBilal A. Mateen Nature Medicine volume 32（8）, pages 3032–3039 53 Integrated care pathway in individuals with Long COVID: STIMULATE‑ICP, a cluster‑randomized, phase 3 trial 长新冠患者综合护理路径：STIMULATE‑ICP整群随机Ⅲ期临床试验 Amitava BanerjeeGordon PrescottYi Mu Nature Medicine volume 32（8）, pages 3040–3047 54 Maternal 6‑valent group B Streptococcus vaccine in non‑pregnant and pregnant females: a randomized phase 1/2 trial B族链球菌六价母体疫苗在非妊娠及妊娠女性中的随机Ⅰ/Ⅱ期临床试验 Shabir A. MadhiHasra SnaggsAlejandra Gurtman Nature Medicine volume 32（8）, pages 3048–3059 55 The genetic architecture of fibromyalgia across 2.5 million individuals 基于250万人群的纤维肌痛遗传结构研究 Isabel KerrebijnGyda BjornsdottirMichael Wainberg Nature Medicine volume 32（8）, pages 3060–3070 56 Povorcitinib for hidradenitis suppurativa: the randomized, double‑blind, placebo‑controlled STOP‑HS1 and STOP‑HS2 phase 3 trials Povorcitinib治疗化脓性汗腺炎：随机双盲安慰剂对照STOP‑HS1、STOP‑HS2两项Ⅲ期临床试验 Martina L. PorterAntonio MartorellChristos C. Zouboulis Nature Medicine volume 32（8）, pages 3071–3081 Analysis（分析） 57 A meta‑analysis of the long‑term effects of antihypertensive therapy on the risk of major cardiovascular disease across 51 randomized trials 纳入51项随机试验的降压治疗对主要心血管病风险长期影响的荟萃分析 Qianqian YangZeinab BidelKazem Rahimi Nature Medicine volume 32（8）, pages 3082–3092 Amendments & Corrections（修订与勘误） 58 Author Correction: SEZ6‑targeting antibody−drug conjugate ABBV‑706 in advanced small cell lung cancer and solid tumors: a phase 1 trial 作者勘误：靶向SEZ6抗体‑药物偶联物ABBV‑706治疗晚期小细胞肺癌及其他实体瘤：Ⅰ期临床试验 Lauren Averett ByersByoung Chul ChoSreenivasa Chandana Nature Medicine volume 32（8）, page 3093 59 Author Correction: MAGE‑A4/MAGE‑A8‑targeted TCR‑based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial 作者勘误：靶向MAGE‑A4/MAGE‑A8的TCR双特异性T细胞衔接分子治疗复发/难治性实体瘤：Ⅰ期临床试验 Martin WermkeSebastian OchsenreitherCarsten Reinhardt Nature Medicine volume 32（8）, page 3094 60 Publisher Correction: Oral small molecule GLP‑1 receptor agonist aleniglipron in people with overweight or obesity: a randomized, double‑blind, placebo‑controlled phase 2b trial 出版方勘误：口服小分子GLP‑1受体激动剂aleniglipron治疗超重/肥胖人群：随机双盲安慰剂对照Ⅱb期临床试验 Julio RosenstockIldiko LingvayBlai Coll Nature Medicine volume 32（8）, page 3095