ABCG1

导 读在感染性疾病研究领域，宿主遗传因素、微生物群调控及免疫机制的交叉作用为破解疾病发病机制提供了新方向。在欧洲临床微生物学与感染病学会全球大会（ESCMID Global 2025）大会上，多项国际前沿研究利用全基因组关联分析、基因组测序、转录组测序以及单细胞测序技术，深入探讨感染性疾病的发病机制以及病原微生物在结直肠癌、宫颈癌、中枢神经系统疾病发生发展中的作用，对于疾病的防治具有重要意义。01分离株全基因组测序、宏基因组测序及宿主转录组分析揭示儿童肺炎支原体感染反弹及耐药株致病机制北京儿童医院的研究人员通过对中国北京、保定地区169株肺炎支原体临床分离株及全球290个公开基因组的全基因组分析，发现北京地区以4-5-7-2 基因型为主（占比超 80%），保定地区则流行4-5-7-2 与 3-5-6-2 基因型（共占 75%）。功能基因富集分析结果显示，4-5-7-2基因型显著富集毒力相关基因，如黏附蛋白的编码基因，且大环内酯类抗生素耐药率接近100%，主要由23S rRNA基因的A2063G突变导致，使得阿奇霉素、红霉素等一线药物失效。这一研究表明，新冠疫情后中国儿童肺炎支原体感染爆发的核心驱动因素为4-5-7-2 等优势基因型的克隆传播及超高的大环内酯耐药率，这为临床紧急调整抗生素策略提供了依据，为后续感染防控与精准治疗奠定基础。同样是针对肺炎支原体，北京儿童医院的另一研究团队则聚焦大环内酯无反应性支原体肺炎（MUMPP），其发生可能与大环内酯耐药肺炎支原体（MRMP）感染、宿主过度免疫反应及其他病原体共感染密切相关。研究人员通过分析MUMPP儿童下呼吸道微生物群及宿主转录组，以揭示MUMPP的潜在致病机制。该研究纳入88例接受大环内酯类抗生素治疗至少3天且无效、后续换用米诺环素的MUMPP儿童，依据支气管镜病理结果分为三组：黏膜侵蚀伴高分泌组（MucES-HS，18 例）、单纯黏膜高分泌组（MucHS，27 例）和正常组（43 例）。结果发现，MucES-HS组的微生物多样性显著低于其他组，提示黏膜侵蚀与下呼吸道微生物多样性降低相关。肺炎支原体在所有组别的下呼吸道微生物群中均占主导地位，其总负荷、相对丰度与外周血炎症指标强相关。宿主转录组的分析结果则表明，肺炎支原体感染可能通过激活宿主固有免疫和炎症反应加剧病情。该研究为解析MUMPP的发病机制提供了新证据，同时强调了结合支气管镜病理分型进行个体化诊疗的重要性。02多组学及单细胞测序揭示牙周梭杆菌通过癸酸-中性粒细胞轴促进结直肠癌发生机制结直肠癌（CRC）是全球高发恶性肿瘤之一，有研究发现，肠道微生物群失衡及免疫失调与CRC的发生发展相关，但具体致病微生物及分子机制尚不明确。北京协和医院的研究团队通过宏基因组学、代谢组学和单细胞转录组测序等技术，对53例CRC患者、35例腺瘤患者及35例健康人的粪便样本以及3例CRC组织、3例癌旁组织和3例腺瘤组织进行多组学整合分析，以探讨宿主与微生物互作在肿瘤发生中的作用。微生物组学结果表明，CRC患者肠道菌群组成及功能发生了显著改变，其中，牙周梭杆菌被最新发现（Fusobacterium periodonticum）在CRC中特异性富集。此外，功能代谢组学结果显示CRC患者中长链脂肪酸合成通路也出现了异常激活，其中癸酸、棕榈酸等代谢物水平与牙周梭杆菌丰度呈显著正相关。同时，单细胞转录组测序发现CRC肿瘤组织中性粒细胞趋化因子CXCL8呈现高表达，以此驱动中性粒细胞相关免疫通路的激活。体外实验及动物实验结果也表明，牙周梭杆菌产生的癸酸可促进中性粒细胞迁移，并上调白细胞迁移及促癌相关基因的表达，其通过调控中性粒细胞浸润促进肠道肿瘤的形成。首次揭示牙周梭杆菌通过合成癸酸驱动中性粒细胞趋化、重塑肿瘤微环境，进而促进结直肠癌发生的新机制。因此，该研究深化了对CRC发病机制的认识，也为利用多组学整合分析来解析复杂疾病提供了范例。03细菌及宿主RNA-seq助力hv-CRKP毒性的机制研究高毒力碳青霉烯耐药肺炎克雷伯菌（hv-CRKP）是医疗相关感染的新威胁，不过，对于其携带的新型质粒“pvirhs1”的致病机制尚不明确。复旦大学华山医院的研究团队采用细菌RNA-seq及小鼠肺RNA-seq，深入探究了pvirhs1质粒在hv-CRKP致病性中的作用。体外实验结果显示，pvirhs1组与肺上皮类器官共培养时，出现了更强的细胞损伤能力；小鼠感染实验中，pvirhs1组小鼠体重下降更显著，肺组织也表现出更广泛的出血、炎症浸润和结构破坏。此外，宿主RNA-seq分析显示，pvirhs1感染组小鼠肺组织中，IL-2、IL-4、IL-8等促炎细胞因子水平显著升高；细菌RNA-seq分析显示铁离子稳态、鞭毛组装及脂多糖生物合成通路显著激活，且其鞭毛长度更长、复杂性更高、黏附能力更强。因此，该研究表明，携带pvirhs1质粒的hv-CRKP通过增强鞭毛和脂多糖合成，强化细菌对宿主细胞的黏附与侵袭能力，同时诱导宿主的过度炎症反应，进而导致更严重的肺部感染。这也提示，临床上需要重视对该质粒的早期检测，以实现感染的精准干预和治疗，降低重症风险。The RNA-seq and cytokine responses in different groups.The bacteria RNA-seq in groups and pilus in the hypervirulent strain04GWAS分析提示ABCG1基因变异与蜱传脑炎易感性相关蜱传脑炎（TBE）是由蜱传脑炎病毒（TBEV）引起的中枢神经系统感染性疾病，临床表现为脑膜炎、脑炎、脊髓炎等。截至目前，宿主的遗传因素在TBE易感性及发病机制中的作用尚不明确。格拉茨医科大学的研究团队对1600例TBE病例和9699例对照进行全基因组关联研究（GWAS），并结合体外功能实验，探索了与TBE易感性相关的关键遗传因素。他们在21号染色体的ABCG1基因内发现两个独立的内含子变异（rs35873421 和 rs3787986），两者与TBE易感性呈显著关联，这两个变异还可以影响ABCG1在外周血中的基因表达。体外实验结果也显示，抑制ABCG1功能或沉默ABCG1的表达，可显著减少TBE病毒在神经元细胞和巨噬细胞中的复制，表明ABCG1对病毒复制具有促进作用。因此，该研究为理解宿主遗传因素对TBE的影响奠定了基础，有望为TBE的精准防治策略开发提供新的思路。05孕期抗生素暴露显著影响阴道耐药基因谱及宫内感染治疗风险宫内感染是导致孕产妇和新生儿发病及死亡的重要原因，而抗生素耐药性的加剧使相关治疗面临更加严峻的挑战。不过，怀孕期间阴道菌群中抗生素耐药基因（ARGs）及其受抗生素暴露的影响尚不清楚。法国鲁昂大学医学院附属医院的研究团队通过对1543名孕妇（1938份阴道样本）孕晚期的阴道样本进行宏基因组分析，发现阴道微生物组中存在547种ARGs，其中60%与b-内酰胺类耐药相关。此外，大环内酯类和四环素类的耐药基因最为丰富，其中lsa(C)和tet(M)是最常见且丰度最高的ARGs。更加重要的是，孕期使用抗生素组在分娩时的b-内酰胺类耐药ARGs丰度较未使用组增加了2倍，其耐药表型多样性也均显著高于未使用组。该研究提示，孕期抗生素的使用可能通过改变阴道耐药组的基因分布和表型谱，进而影响宫内感染的治疗策略，因此需进一步关注耐药表型多样性在临床中的潜在风险。06单细胞RNA测序揭示伯氏疏螺旋体逃避宿主免疫机制伯氏疏螺旋体（Borrelia burgdorferi）是引发莱姆病的病原体，作为北半球最常见的虫媒传染病，其感染会触发宿主固有免疫和适应性免疫反应，但宿主难以清除病原体，导致细菌持续存在并通过蜱媒传播。芬兰图尔库大学的研究人员借助单细胞转录组测序，发现伯氏疏螺旋体感染小鼠的生发中心在感染早期被快速启动，但随后被抑制，表现为B细胞中抗原呈递相关基因表达下调，抗体类别转换偏向IgG3、IgG2b、IgG2c 亚类（非中和性抗体），而保护性 IgG1 亚类则出现了下降。此外，细胞通讯与调控也出现了异常，例如，调节性T细胞和滤泡调节性T细胞活性升高，分泌IL-10等抑制性细胞因子；B细胞中Socs1和Socs3持续高表达，阻断 JAK-STAT 信号通路，抑制B细胞活化及生发中心分化，导致T-B细胞间通讯受阻等。因此，该研究揭示了伯氏疏螺旋体通过操纵生发中心进而逃避宿主免疫防御，为理解莱姆病慢性感染的免疫逃逸机制提供了新视角。07嗜血杆菌属在COPD急性加重期通过菌群失衡等加剧病情慢性阻塞性肺疾病（COPD）是与呼吸道微生物组成密切相关的呼吸系统疾病，虽然有研究表明流感嗜血杆菌与COPD的急性加重（AECOPD）相关，但嗜血杆菌属在COPD不同疾病阶段的作用及特征尚不明确。西班牙巴塞罗那贝尔维特医院的研究团队对57例COPD患者（其中24例为AECOPD、19例为稳定期频繁急性加重、14例为稳定期非急性加重）的痰样本进行分析，旨在揭示嗜血杆菌属在疾病发生发展中的关键作用。研究结果表明，AECOPD组微生物多样性显著降低，其中，该研究嗜血杆菌属是唯一在AECOPD组相对丰度显著高于稳定期的菌属，而流感嗜血杆菌的存在与该属丰度升高密切相关。进一步的分析发现，流感嗜血杆菌与副流感嗜血杆菌存在遗传异质性，后者抗菌耐药性显著更高，且两者携带不同耐药相关基因突变。因此，证实嗜血杆菌属在COPD发病机制中具有关键作用，尤其在AECOPD期通过流感嗜血杆菌增殖和微生物多样性降低加剧菌群失衡。08脑肿瘤患者肠道菌群研究近年来，肠脑轴在中枢神经系统（CNS）疾病中的作用日益受到关注，但其在脑肿瘤发生发展中的具体机制仍不明确。土耳其埃尔吉耶斯大学的研究人员通过16S rRNA测序对比鞍区/鞍旁肿瘤、其他脑肿瘤患者与健康人的肠道微生物组成及代谢特征，探索微生物在CNS肿瘤中的潜在作用。通过ROC曲线评估标志物的鉴别效能，重点分析相对丰度数据对诊断效能的影响。研究结果表明，健康人肠道菌群多样性显著高于脑肿瘤患者，集与免疫调节相关的有益菌属（如毛螺菌属、粪杆菌属），而肿瘤组则以芽孢杆菌属等促炎菌种为主。研究发现，结合细菌相对丰度数据可显著增强诊断的效能，例如毛螺菌属AUC 从0.50提升至0.76；拟杆菌属从0.56提升至0.73。而粪杆菌属的AUC始终稳定在0.93，不受丰度影响。该研究为开发基于微生物的诊断和治疗策略、架起肠道菌群研究与CNS肿瘤研究的桥梁奠定了基础。09宿主+病原宏转录组分析揭示NSTIs中的病原-宿主互作坏死性软组织感染（NSTIs）是一类病情凶险、进展迅速的严重感染性疾病，且宿主与病原体的分子互作机制仍未被充分解析。来自印度的研究团队采用宿主及病原宏转录组分析（Meta-transcriptome analysis）策略，对3例健康组织活检样本与3例NSTI坏死组织样本进行对比分析，结果发现NSTI样本与健康样本的基因表达模式存在显著差异，NSTI样本中检测到23831个下调转录本和3066个上调转录本，下调基因数量约为上调基因的8倍，提示宿主防御相关功能可能被广泛抑制。通路富集分析同样表明NSTI样本中多条生物学通路显著下调，提示宿主在感染过程中可能出现免疫应答、组织修复等关键功能的失调。该研究通过宏转录组分析首次揭示了NSTIs中广泛存在的基因表达失调和通路破坏，为理解多微生物感染如何重塑宿主转录组提供了新视角。10嗜麦芽窄食单胞菌通过线粒体功能紊乱驱动宫颈癌进展宫颈癌是全球女性高发恶性肿瘤，研究表明，人乳头瘤病毒（HPV）感染与宫颈微生物群动态变化共同参与肿瘤进展，但微生物在宫颈癌发生中的具体作用及与宿主的互作机制尚不明确。来自印度的一项研究通过分析正常宫颈、癌前病变及宫颈癌组织的微生物组、抗生素耐药基因及宿主细胞功能变化，探讨了关键致病细菌在宫颈癌进展中的潜在作用。研究表明，宫颈微生物群随癌症进展显著失调，与正常宫颈相比，宫颈癌组织中嗜麦芽窄食单胞菌、肺炎克雷伯菌等致病菌丰度显著升高，而乳酸杆菌属等有益菌显著减少，微生物多样性也下降了40%。进一步的研究发现，嗜麦芽窄食单胞菌通过线粒体功能紊乱促癌，同时，肺炎克雷伯菌和嗜麦芽窄食单胞菌的生物膜产量较正常组高出2-3倍，且与抗生素耐药基因变异呈正相关。该研究首次证实嗜麦芽窄食单胞菌通过调控线粒体功能和诱导氧化应激参与宫颈癌进展，也深化了对宿主-微生物互作驱动肿瘤发生的认识，为开发基于微生物的宫颈癌防治策略奠定了基础。11ARPI治疗前列腺癌对肠道微生物群的扰动前期有研究表明，前列腺癌（PC）的发生发展与肠道微生物群密切相关，雄激素受体通路抑制剂（ARPI）作为转移性前列腺癌的常用治疗药物，其对肠道微生物群的潜在影响尚不清楚。西班牙维戈大学附属医院的研究人员采用鸟枪法测序对接受ARPI治疗的转移性前列腺癌患者的肠道微生物群特征进行了分析，结果发现，ARPI治疗组的微生物丰富度显著低于未治疗组，两组的b多样性也存在显著的差异。ARPI治疗组的Butyricimonas、Enterocloster、Flavonifractor、Sutterella等菌属丰度显著降低，而Alistipes merdavium、Intestinibacter则显著富集，其PI3K-AKT信号通路（细胞存活相关）显著下调，而与二氢睾酮合成相关的通路则出现了富集。总之，该研究发现接受ARPI治疗的转移性前列腺癌患者存在肠道微生物群失调，因此，监测肠道微生物群的动态变化可为前列腺癌个体化治疗提供依据。结语总之，上述这项研究不仅深化了对感染性疾病、肿瘤等复杂疾病发病机制的认知，更在耐药性防控、微生物靶向治疗、遗传风险评估等领域提供了创新思路，为推动精准医疗与个体化诊疗策略的研发奠定了重要基础。参考来源：1.ESCMID Global 2025 L0026 Genome-wide association study identifies ABCG1 as a susceptibility locus for tick-borne encephalitis.2.ESCMID Global 2025 O0129 Multi-omics integrated analysis revealed the key role of Fusobacterium periodonticum in colorectal tumorigenesis by decanoic acid-promoting neutrophil chemotaxis.3.ESCMID Global 2025 O0130 Exploring the respiratory microbiome in COPD patients: the role of Haemophilus spp. in disease pathogenesis.4.ESCMID Global 2025 O0193 Antibiotic resistance genes diversity and antimicrobial effects in the vaginal microbiome during pregnancy.5.ESCMID Global 2025 O0194 Distinct gut microbiota and metabolic profiles in brain tumor patients: bridging microbial insights to CNS oncology.6.ESCMID Global 2025 O0868 Bacteria and host responses in both mice and human lung organoid model revealed the role of a novel plasmid pvirhs1 in hypervirulent carbapenem-resistant Klebsiella pneumoniae.7.ESCMID Global 2025 O0870 Meta-transcriptomic insights into host-pathogen interactions in necrotising soft tissue infections using differential analysis.8.ESCMID Global 2025 P0909 Whole-genome analysis unveils genetic factors driving the Mycoplasma pneumoniae outbreak among children post-COVID-19 in China.9.ESCMID Global 2025 P0912 Integrated study of respiratory microbiota and host response in children with macrolide-unresponsive Mycoplasma pneumoniae pneumonia.10.ESCMID Global 2025 P1017 Microbiome analysis of cervical cancer identified Stenotrophomonas as a potential pathogen involved in tumor progression.11.ESCMID Global 2025 P3461 Gut microbiota in patients with metastasic prostate cancer: analysis of potential effects of androgen receptor pathway inhibitors.12.ESCMID Global 2025 P3549 Single-cell profiling of T-dependent immune response of Borrelia burgdorferi infection in a murine model.* 本文转自测序中国公众号.

*仅供医学专业人士阅读参考 过犹不及，属实是放之四海而皆准的道理，就拿细胞癌变来说，许多时候癌变的发生，就是因为要应对时时刻刻都在发生的组织损伤，人体内相应不断重复的组织修复过程“过了”，其中的差错乃至失控就会为随后的癌变埋下伏笔[1]。而这种小概率的不幸，就最常发生在各种与外界接触的屏障组织，毕竟接触多损伤就多嘛。 但正如奇点糕所说，这种不幸毕竟是小概率事件，不然各种癌症就满天飞了，换句话说，人体内存在着能将正常组织修复和癌变区隔开来的调控机制。而近日，瑞典卡罗林斯卡学院研究者们在《自然》上发表的最新研究成果就证明了这一点：肠道中的肝脏X受体（LXR）通路，就是既能促进肠道上皮细胞在损伤后再生，又能抑制肠癌发生的一种调控机制[2]！ 研究发现，在组织损伤需要修复时，LXR通路激活可使肠上皮细胞产生促修复的关键调控因子双调蛋白（amphiregulin, AREG）；但换到癌症场景中，LXR通路的激活则会调动适应性免疫应答抗癌，因此激活LXR通路就成为了一种既能促进组织再生，又不增加癌变风险的干预策略，这既可以帮助癌症患者，也可以用于炎症性肠病（IBD）等疾病的治疗。 一图总结论文主要发现 通过分析既往研究中，以放射线和葡聚糖硫酸钠诱导（后者常用于肠炎建模）小鼠小肠损伤后，小肠组织基因表达的改变，研究者们找到了4个受LXR调控的靶基因（Abca1, Apoc3, Apoa1和Apoa4），并在小鼠实验中用LXR激动剂证实，LXR通路激活可加快小鼠肠道损伤后的修复（如增加隐窝面积），且Abca1和Abcg1两个靶基因表达被明显诱导上调。 当然了，修复损伤后的组织和保护肠道不受损伤，是完全不同的两个概念，研究者们也专门分析证实，LXR通路激活的作用出现在损伤发生后，且促修复作用还不会使肠道内发生炎症反应或免疫细胞聚集，这也是一种降低风险的保护效应了。而在组织修复过程中必不可少的，则是被LXR通路激活促表达的双调蛋白。 激活LXR通路可在肠道损伤发生后起到促修复作用 而在LXR的上游，能够在肠道损伤发生后进行感知并将LXR激活的，则是CYP450单加氧酶家族成员CYP27A1，它会在放射线或DSS诱导肠道损伤后表达率先上调（最先发生在隐窝，此后是肠上皮固有层），而CYP27A1的作用就是产生LXR的配体27-羟基胆固醇（27-HC），配体多了，LXR通路当然就能活跃起来。 CYP27A1的表达上调是LXR通路激活的上游事件 加速损伤修复当然是好事，但奇点糕一开始也说过，癌细胞特别是癌症干细胞，有时候真会明晃晃地劫持正常的组织修复机制，用来帮自己无休止地增殖和进展，正如两百年前西方学者所说，“癌症是一种永不愈合的伤口”。如果要以激活LXR通路作为一种治疗手段，它是否会增加正常组织的癌变风险，也是必须要弄清楚的。 LXR，能Hold住吗？ 本次研究的最后一部分，就在这个问题上收获了惊喜：研究者们发现，向自发性肠癌模型小鼠喂食LXR激动剂，就可显著减少小鼠肠道内的腺瘤数量和体积，而敲除Cyp27a1则作用恰好相反，这意味着CYP27A1-LXR通路确实能限制肠癌发生。空间转录组学分析显示，激活LXR通路可有效促进三级淋巴结构（TLS）形成，由此利好适应性抗肿瘤免疫应答，且这种免疫应答可能是由B细胞主导、T细胞辅助的。 CYP27A1-LXR通路能够限制肠癌发生 总而言之，激活LXR通路能加速肠道屏障修复、且不增加癌变风险，这对于炎症性肠病等疾病患者来说前景也太美好了，而卡罗林斯卡学院的研究者们还表示，对于放化疗等原因导致的肠道屏障受损，激活LXR通路或许也能加速修复，减少相关的治疗并发症，那，期待+1~ 参考文献： [1]Ge Y, Gomez N C, Adam R C, et al. Stem cell lineage infidelity drives wound repair and cancer[J]. Cell, 2017, 169(4): 636-650. e14. [2]Das S, Parigi S M, Luo X, et al. Liver X receptor unlinks intestinal regeneration and tumorigenesis[J]. Nature, 2024. 本文作者丨谭硕

LA JOLLA, Calif., May 28, 2024 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ: MNOV) and the Standard Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that MediciNova conducted two poster presentations at the 92nd European Atherosclerosis Society (EAS) 2024 Congress held online May 26-29, 2024. MediciNova’s Chief Medical Officer, Kazuko Matsuda, MD PhD MPH presented an update on the Company’s “STUDY PROTOCOL TO EVALUATE MN-001’S (TIPELUKAST) EFFICACY, SAFETY AND TOLERABILITY IN SUBJECTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) (Abstract # 810) “, which included Clinical background, Study objectives, Study design, Inclusion Criteria and Study status of Phase 2 clinical trial ongoing in the US. As of 25 April 2024, 33 patients were enrolled, 19 patients were randomized, 14 patients completed the study. Three subjects reported serious adverse events (SAE) and were all considered “Unlikely related” or “Unrelated“ to study drug. MediciNova’s Dr. Huicheng Qi presented “MN-002, THE METABOLITE OF MN-001 (TIPELUKAST) PROMOTES MACROPHAGE CHOLESTEROL EFFLUX (Abstract # 856)”, demonstrating positive data regarding cholesterol efflux capacity by MN-001 (Tipelukast) and MN-002. This is a collaborative effort between MediciNova and Professor Masatsune Ogura at Department of Clinical Laboratory Technology, Juntendo University and Professor Takashi Miida at Department of Clinical Laboratory Medicine, Juntendo University. Objectives of this study are to evaluate the effects of MN-001 and its major active metabolite MN-002 on cholesterol efflux capacity in THP-1 *1macrophages. ABCA1 *2 and ABCG1 *3 is known to play important roles in the reverse cholesterol transport system. Macrophages derived from THP-1 *3 cells were used to analyze the effect of MN-001 and MN-002 on ABCA1 and ABCG1 mRNA expression was measured by RT-PCR and protein expression was measured by Western blotting. Next, the effects of MN-002 on Apolipoprotein AI (ApoA1) *4 dependent and High-Density Lipoprotein (HDL) dependent cholesterol efflux in THP-1 macrophages were determined, respectively. Finally, analyzed the involvement of Protein Kinase A (PKA) in the mechanism of action of MN-002 using a PKA inhibitor. The data presented in the abstract demonstrated the following: MN-002 enhances ApoA1 and HDL mediated cholesterol efflux. MN-002 increased 44.3% in ApoA1-mediated cholesterol efflux capacity compared to the control group (DMSO). MN-002 increased 15.3% in HDL-mediated cholesterol efflux capacity compared to the control group (DMSO). MN-002 increases ABCA1 and ABCG1 protein levels in dose-dependent manner MN-002 increased ABCA1 protein expression in a dose-dependent manner compared to the control group (DMSO); ABCA1 protein increased approximately 2-fold with 10 µM of MN-002. MN-002 increased ABCG1 protein expression in a dose-dependent manner compared to the control group (DMSO); ABCG1 protein increased approximately 2.8-fold with 10 µM of MN-002. MN-002 increases ABCA1/ ABCG1/ LXR-alpha mRNA levels. MN-002 increased ABCA1 mRNA expression in a time and dose-dependent manner compared to the control group (DMSO). mRNA expression of ABCA1 increased about 3-fold with 24 hours exposure of 10 µM MN-002. MN-002 increased ABCG1 mRNA expression in a time and dose-dependent manner compared to the control group (DMSO). mRNA expression of ABCA1 by increased 5.4-fold with 24 hours exposure of 10 µM MN-002 MN-002 increased LXR-alpha mRNA expression in a time- and dose-dependent manner compared to the control group (DMSO). mRNA expression of ABCA1 increased 2.4-fold with 24 hours exposure of 10 µM MN-002. MN-002 increases ABCA1 protein level independent of PKA signaling pathway. MN-002 increased ABCA1 protein expression compared to the control group (DMSO); conditions in which a PKA inhibitor did not cancel the effect of MN-002 to increase ABCA1 protein expression. Kazuko Matsuda, M.D., Ph.D., M.P.H., Chief Medical Officer, MediciNova, Inc., commented, “We are very pleased to present our clinical trial status and positive research outcomes at the EAS Congress 2024. We have randomized almost half of the randomization goal with our ongoing Phase 2 clinical trial. With the collaborative research with Juntendo University regarding the mechanism of action of MN-001/MN-002 in lipid metabolism, we identified that MN-002, the major metabolite of MN-001 (Tipelukast), had significant positive effects on both ABCA1, ABCG1 expression.” *1 About THP-1 THP-1 is a human leukemia monocytic cell line, which has been extensively used to study monocyte/macrophage functions, mechanisms, signaling pathways, and nutrient and drug transport. *2 About ABCA1: ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis. ABCA1 is an integral cell membrane protein that protects against cardiovascular disease. *3 About ABCG1 The primary function of ATP-binding cassette transporter G1 (ABCG1) is to efflux cholesterol to spherical high-density lipoproteins (HDL). ABCG1 also effluxes cholesterol to low-density lipoproteins (LDL), liposomes and cyclodextrin and it exports sphingomyelin, phosphatidylcholine and oxysterols to HDL and albumin. *4 About Apolipoprotein AI (ApoA1) Apolipoprotein A-I (Apo A-I) is a major protein that has specific roles in the lipid metabolism. It promotes cholesterol efflux by accepting fats from cells to the liver for excretion. AboutNAFLD,Type2DiabetesMellitus(T2DM),andHypertriglyceridemia NAFLD is considered the hepatic manifestation of metabolic syndrome; studies have reported that 50% of patients with metabolic syndrome also have NAFLD. There is sufficient clinical and epidemiological evidence supporting the assertion that NAFLD is strongly associated with an increased prevalence and incidence of cardiovascular disease, T2DM, chronic kidney disease, and malignancy. The presence of dyslipidemia (hypercholesterolemia, hypertriglyceridemia, or both) is reported in 20 - 80% of NAFLD cases. AboutMN-001 MN-001 (tipelukast) is a novel, orally bioavailable, small molecule compound thought to exert its effects through several mechanisms to produce its anti-inflammatory and anti-fibrotic activity in preclinical models, including leukotriene (LT) receptor antagonism, inhibition of phosphodiesterases (PDE) (mainly 3 and 4), and inhibition of 5-lipoxygenase (5-LO). The 5-LO/LT pathway has been postulated as a pathogenic factor in fibrosis development, and MN-001's inhibitory effect on 5-LO and the 5-LO/LT pathway is a novel approach to treat fibrosis. MN-001 has been shown to down-regulate expression of genes that promote fibrosis including LOXL2, Collagen Type 1 and TIMP-1. MN-001 has also been shown to down-regulate expression of genes that promote inflammation including CCR2 and MCP-1. In addition, MN-001 was found to inhibit triglyceride synthesis in hepatocytes by inhibiting arachidonic acid uptake. About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety pro MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in Long COVID and substance dependence. MN 001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by, or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2023 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT: David H. Crean, Ph.D. Chief Business Officer MediciNova, Inc info@medicinova.com