Azacitidine

FY 2025 sales growth of 10.9% at CER 1 , or 8.1% as reported, driven by growth of the three therapeutic areas of Oncology (4.1% 1 ), Rare Disease (102.5% 1 ) and Neuroscience (9.7% 1 ); Somatuline® sales growth of 4.3% 1 , with all other products, excluding Somatuline, achieving double-digit sales growth of 14.2% 1 FY 2025 core operating income of €1,294m, growing by 16.7% as reported, with a core operating margin of 35.2% of total sales, increasing by 2.6 points 2025 continued pipeline expansion, driven by significant regulatory and clinical milestones, integration of multiple preclinical assets with global rights and innovative approaches, and a mid-stage candidate from the acquisition of ImCheck Therapeutics Five major regulatory and clinical milestones expected in 2026, in addition to the full data readout for IPN10200 in an aesthetics indication Financial guidance 2 for 2026 including total sales growth greater than 13.0% 3 at CER, assuming an acceleration of our portfolio excluding Somatuline as well as the growth of Somatuline due to generic lanreotide production challenges, and core operating margin greater than 35.0% of total sales PARIS, FRANCE, 12 February 2026 - Ipsen (Euronext: IPN; ADR: IPSEY), a global specialty-care biopharmaceutical company, today presents its financial results for the full year (FY) 2025 and for the fourth quarter of 2025. Extract of consolidated results 4 for FY25 and FY24 FY 2025 FY 2024 % change €m €m Actual CER Total Sales 3,675.9 3,400.6 8.1 % 10.9 % Core Operating Income 1,294.1 1,109.4 16.7 % Core operating margin 35.2 % 32.6 % +2.6pts Core Consolidated Net Profit 1,009.1 857.8 17.6 % Core earnings per share (fully diluted) €12.09 €10.27 17.8 % IFRS Operating Income 625.9 496.7 26.0 % IFRS operating margin 17.0 % 14.6 % +2.4pts IFRS Consolidated Net Profit 444.5 347.3 28.0 % IFRS earnings per share (fully diluted) €5.32 €4.15 28.3 % Free Cash Flow 1,000.6 774.4 29.2 % Closing net cash/(debt) 559.9 160.3 n/a “In 2025, Ipsen delivered strong sales and profit growth,” said David Loew, Chief Executive Officer, Ipsen. “We continued to execute across all three therapeutic areas, with a notable performance from Iqirvo. We have advanced multiple pipeline programs and further strengthened our innovation engine through targeted business development, including the acquisition of Imcheck Therapeutics. We also achieved promising proof-of-concept for IPN10200, our first-in-class differentiated long-acting recombinant molecule. We are expecting another year of double-digit sales growth for 2026, supported by accelerated performance across the entire portfolio and a better outlook for Somatuline given the production challenges faced by generic competition. We anticipate five regulatory and clinical milestones this year and to further deliver on our external innovation strategy.” Full-year 2026 guidance and mid-term outlook Ipsen has set for FY 2026 the following financial guidance: Total sales growth greater than 13.0%, at constant currency. Based on the average level of exchange rates in January 2026, an adverse effect on total sales of around 2% of currencies is expected Core operating margin greater than 35.0% of total sales, which includes additional R&D expenses from anticipated early and mid-stage external-innovation opportunities Guidance on total sales and core operating margin is assuming accelerated sales growth of the portfolio excluding Somatuline and the growth of Somatuline sales due to generic lanreotide challenges. It excludes any impact from potential late-stage (Phase III clinical development or later) business development transactions. As part of its ongoing review of long-term assumptions including competitive intensity and product lifecycle considerations, Ipsen no longer expects to achieve the €500m peak sales for Onivyde and Tazverik. Based on higher expected Somatuline sales due to continued generic lanreotide production challenges and the performance of the broader portfolio, Ipsen is highly confident on its 2027 mid-term outlook to exceed the total-sales average growth 5 of at least 7% per year for the period 2023-27 and core operating margin in 2027 of at least 32% 6 of total sales. Pipeline progress During 2025, Ipsen achieved a number of important regulatory and clinical milestones across its portfolio, reflecting continued advancement of its pipeline across the three therapeutic areas. In the first quarter of 2025, the regulatory filing for tovorafenib, an oral, type II RAF-kinase inhibitor for pediatric low-grade glioma, was accepted for review by the European Medicines Agency (EMA). In May 2025, Ipsen presented Phase II data from the ELMWOOD study of Iqirvo® (elafibranor) at the European Association for the Study of the Liver (EASL) Congress, demonstrating a favorable safety pro dose-dependent efficacy over 12 weeks in people living with primary sclerosing cholangitis, a condition with high unmet medical need. In July 2025, the European Commission approved Cabometyx® (cabozantinib) for the treatment of previously treated advanced neuroendocrine tumors (NETs), based on positive results from the Phase III CABINET trial. In September 2025, positive Phase II data from the LANTIC trial in aesthetics were reported, demonstrating a differentiated, long-acting clinical pro IPN10200. During the year, Ipsen also initiated a Phase II study of IPN10200 in cervical dystonia, representing the fourth clinical study in the development plan of the global long-acting recombinant molecule across therapeutic and aesthetic indications. In December 2025, Ipsen announced that the pivotal Phase II FALKON trial of fidrisertib in fibrodysplasia ossificans progressiva (FOP) did not meet its primary endpoint and that the study was subsequently closed; fidrisertib was generally well-tolerated, with no safety concerns identified. In addition, Ipsen initiated multiple Phase I oncology studies across IPN01195, a RAF inhibitor, the antibody-drug conjugate IPN60300 and the T-cell activator IPN01203, further strengthening its targeted oncology pipeline. External innovation In December 2025, Ipsen expanded its immuno-oncology portfolio with the acquisition of ImCheck Therapeutics, a biotechnology company developing next-generation immuno-oncology therapies including IPN60340 (ICT01), a first-in-class monoclonal antibody targeting BTN3A, currently in Phase I/II development, with a Phase IIb/III study planned to start in 2026. IPN60340 has the potential to be a new standard of care in combination in first line unfit acute myeloid leukemia, an aggressive blood cancer affecting older adults. Interim data orally presented at the annual American Society of Clinical Oncology 2025 from the Phase I/II EVICTION trial showed treatment with ICT01 in combination with venetoclax and azacitidine (Ven-Aza) achieved very encouraging high responses. In this single-arm trial, treatment response nearly doubled relative to those seen in historical standard-of-care data across all molecular subtypes in newly diagnosed patients including sub-types typically less responsive to standard-of-care (Ven-Aza). In January 2026, Ipsen also announced that IPN60340 received U.S. FDA Breakthrough Therapy Designation in first-line unfit acute myeloid leukemia. In December 2025, Ipsen further strengthened its oncology and early-stage pipeline through two additional targeted business development and research collaborations. Ipsen entered into an exclusive licensing agreement with Simcere Zaiming for rights outside Greater China to SIM0613, an antibody–drug conjugate (ADC) targeting LRRC15. Ipsen also announced a new research collaboration and option agreement with the Université de Montréal and IRICoR, encompassing two discovery-stage programs focused on novel inhibition of pathways complementary to the MAP kinase pathway. 2026 Upcoming Milestones Ipsen anticipates several key milestones across its portfolio in 2026, including: Tovorafenib (FIREFLY-1) - European regulatory decision for pediatric low-grade glioma Bylvay (BOLD) - Readout of pivotal Phase III in biliary atresia Iqirvo (ELSPIRE) - Readout of pivotal Phase III in primary biliary cholangitis Dysport (BEOND) - Readout of pivotal Phase III trials in chronic and episodic migraine IPN10200 (LANTIC) - Readout of Phase II in lateral canthal lines and forehead lines These milestones reinforce Ipsen’s commitment to advancing innovative therapies and expanding treatment options for patients worldwide. Full data from the Phase II LANTIC study of IPN10200, which demonstrated a positive first-in-class, differentiated long-acting clinical pro the initiation of Phase III, are expected to be presented in the first half of 2026 at an upcoming congress. Galderma arbitration In January 2026, the Arbitral Tribunal of the International Chamber of Commerce (ICC) issued a final decision in favor of Ipsen, dismissing the claim brought by Galderma in connection with Ipsen’s termination of the R&D agreement. The Tribunal confirmed Ipsen’s full rights to its clinical-stage toxin programs in the aesthetics field, including IPN10200. Ipsen continues to assess all options to maximize the value of its long-acting program. Environmental, Social and Governance Ipsen took important steps in 2025 to deliver its ambitious sustainability strategy, continuing to embed sustainability across its operations and decision-making. From reducing its environmental footprint to advancing patient access and strengthening its workplace culture, Ipsen reinforced its commitment to delivering progress for patients, employees, communities, and the planet. Ipsen made good progress across multiple environmental targets, including: 54% reduction in Scopes 1 & 2 greenhouse gas emissions (vs. a 2019 baseline) 16% reduction in Scope 3, fully in line with our 2030 targets (vs. a 2019 baseline) 100% of Ipsen’s global electricity now comes from renewable sources 55% of the company fleet now comprised of electric vehicles as of 2025 through the Fleet for Future Project Ipsen received an A rating from CDP for our best-practice environmental actions and transparency, and for demonstrating our comprehensive understanding of environmental dependencies, risks, and opportunities. Ipsen is proud to be one of the first biopharmaceutical companies to achieve full gender parity within the Executive Leadership Team, and with women now representing 53% of the Global Leadership Team. Consolidated financial statements The Board of Directors approved the consolidated financial statements on 11 February 2026. The consolidated financial statements have been audited, and the Statutory Auditors’ report is in the process of being published. Ipsen’s comprehensive audited financial statements will be available on ipsen.com in due course, under the Reports and Accounts tab in the Investor Relations section. Conference call A conference call and webcast for investors and analysts will begin today at 2pm CET. Participants can access the webcast here . Analysts can join the call and ask questions by registering here . Calendar Ipsen intends to publish its Q1 2026 sales on April 23rd, 2026. Notes All financial figures are in € millions (€m), unless otherwise noted. The performance shown in this announcement covers the twelve-month period to 31 December 2025 (FY 2025) and the three-month period to 31 December 2025 (Q4 2025), compared to the twelve-month period to 31 December 2024 (FY 2024) and the three-month period to 31 December 2024 (Q4 2024), respectively, unless stated otherwise. The commentary is based on the performance in FY 2025, unless stated otherwise. About Ipsen We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience. Our pipeline is fueled by internal and external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 100 countries. Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com . Ipsen Contacts Investors Henry Wheeler henry.wheeler@ipsen.com +33 7 66 47 11 49 Khalid Deojee khalid.deojee@ipsen.com +33 6 66 01 95 26 Media Sally Bain sally.bain@ipsen.com +1 857 320 0517 Anne Liontas anne.liontas.ext@ipsen.com +33 7 67 34 72 96 Disclaimers and/or forward-looking statements The forward-looking statements, objectives and targets contained herein are based on Ipsen’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. All of the above risks could affect Ipsen’s future ability to achieve its financial targets, which were set assuming reasonable macroeconomic conditions based on the information available today. Use of the words ‘believes’, ‘anticipates’ and ‘expects’ and similar expressions are intended to identify forward-looking statements, including Ipsen’s expectations regarding future events, including regulatory filings and determinations. Moreover, the targets described in this document were prepared without taking into account external-growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by Ipsen. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties, notably the fact that a promising medicine in early development phase or clinical trial may end up never being launched on the market or reaching its commercial targets, notably for regulatory or competition reasons. Ipsen must face or might face competition from generic medicine that might translate into a loss of market share. Furthermore, the research and development process involves several stages each of which involves the substantial risk that Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Other risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation and risks arising from unexpected regulatory or political changes such as changes in tax regulation and regulations on trade and tariffs, such as protectionist measures, especially in the United States; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen cannot be certain that its partners will fulfil their obligations. It might be unable to obtain any benefit from those agreements. A default by any of Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen expressly disclaims any obligation or undertaking to update or revise any forward-looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. Ipsen’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers. The risks and uncertainties set out are not exhaustive and the reader is advised to refer to Ipsen’s latest Universal Registration Document, available on ipsen.com . 1 At constant exchange rates (CER), which exclude any foreign-exchange impact by recalculating the performance for the relevant period by applying the exchange rates used for the prior period. 2 Excluding any impact from potential late-stage (Phase III clinical development or later) external-innovation transactions. 3 Based on the average level of exchange rates in January 2026, an adverse impact on total sales of around 2% from currencies is expected. 4 Extract of consolidated results. The Company’s auditors performed an audit of the consolidated financial statements. 5 CAGR 2023-2027 at constant exchange rates. 6 Excluding any impact from potential late-stage (Phase III clinical development or later) external-innovation transactions. Attachment Ipsen PR_FY 2025 Results Announcement_12022026

写在前面 今天推荐的是重庆大学生物工程学院、云南癌症医院肝胆胰外科团队于 2024 年发表于《Signal Transduction and Targeted Therapy》（2024IF：38.1，JCR Q1）的一篇综述，通讯作者是宋冠斌（Guanbin Song）教授。研究聚焦染色质可及性的生物学功能、分子调控机制及疾病治疗应用，系统整合其在生理病理过程中的核心作用，揭示染色质动态调控作为疾病精准治疗靶点的潜力，为表观遗传领域的转化医学研究提供全新框架。 研究背景 染色质是真核生物基因组的载体，由 DNA、组蛋白、非组蛋白及少量 RNA 组成，可分为高度浓缩的异染色质（染色质不可及区域）和松散分布的常染色质（染色质可及区域），核小体作为基本结构单元，其分布与占据状态是染色质可及性的核心决定因素。染色质可及性指核内大分子与染色质化 DNA 的物理接触许可性，直接影响 DNA 转录、复制及损伤修复等关键生物学过程，仅占全基因组 2%-3% 的可及区域承载了超过 90% 的转录因子结合位点，是基因表达调控的核心枢纽。正常的染色质可及性动态平衡对维持机体稳态至关重要，其异常调控与心血管疾病、肿瘤、神经系统疾病、糖尿病等多种疾病的发生发展密切相关。尽管目前已开发基于酶切、转座酶等原理的多种染色质可及性检测技术，但染色质可及性的多层级调控网络（遗传、表观遗传、环境因素等）及其在不同生理病理场景下的特异性机制尚未被系统阐明，针对染色质动态调控的靶向治疗策略仍需深入探索，为填补这一空白，本综述进行了全面整合与解析。 摘要部分 染色质可及性的动态调控是真核基因组的显著特征，其状态由核小体分布、组蛋白修饰、DNA 甲基化、非编码 RNA、染色质三维结构等多因素共同决定，直接影响 DNA 转录、复制及损伤修复等核心生物学过程。该综述系统阐述了染色质可及性在不同生理病理过程中的核心功能与调控机制：生理层面，染色质可及性参与胚胎发育、器官形成、组织再生、昼夜节律及衰老等过程，通过细胞类型特异性调控网络塑造细胞命运；病理层面，其异常与肿瘤、心血管疾病、肝脏疾病、神经系统疾病、糖尿病等多种疾病的发病机制密切相关，尤其在肿瘤的发生、增殖、转移、干细胞特性维持及免疫逃逸中发挥关键作用。此外，综述总结了基于染色质可及性调控的治疗策略，包括靶向核小体重塑复合物、DNA 甲基化修饰酶、组蛋白修饰酶及转录因子等的抑制剂开发。总体而言，染色质可及性是连接基因组功能与细胞微环境的核心枢纽，其动态调控机制的解析为疾病诊断提供了潜在生物标志物，也为开发精准靶向治疗策略奠定了理论基础，未来需进一步突破技术瓶颈，推动临床转化应用。 研究内容 1. 染色质可及性的核心调控机制 染色质可及性的动态平衡由多重调控机制协同维持，核心包括核小体重塑、DNA 甲基化、组蛋白修饰、先锋转录因子、非编码 RNA、顺式调控元件、染色质三维结构及环境因素等：核小体重塑复合物（SWI/SNF、NuRD、ISWI、INO80 家族）依赖 ATP 水解能量调控核小体动员，其中 SWI/SNF 复合物通过 BRG1/BRM 等核心亚基调控基因转录，NuRD 复合物兼具组蛋白去乙酰化和核小体重塑活性，ISWI 家族主要介导核小体重定位，INO80 家族参与转录激活及 DNA 损伤修复；DNA 甲基化通过 DNMTs 催化的甲基化与 TETs 介导的去甲基化动态平衡调控染色质可及性，甲基化通常阻碍转录因子结合，而去甲基化则增强区域染色质开放性；组蛋白修饰（磷酸化、甲基化、泛素化、酰化等）通过改变组蛋白与 DNA 的结合亲和力或招募调控因子，直接影响染色质状态，如组蛋白乙酰化减弱组蛋白正电荷，增强染色质可及性，而 H3K9me3、H3K27me3 等甲基化修饰则通常与染色质浓缩相关；先锋转录因子（如 FoxA 家族、Sox9 等）可结合闭合染色质区域并增强局部可及性，为其他组织特异性转录因子结合创造条件；非编码 RNA（miRNA、lncRNA、circRNA）通过与染色质重塑复合物相互作用或中和组蛋白正电荷，调控染色质可及性；顺式调控元件的 DNA 序列特征及单核苷酸多态性决定转录因子结合亲和力，进而影响染色质状态；染色质三维结构（如 TADs、环结构）通过 CTCF 和 cohesin 蛋白介导的边界调控，影响区域染色质可及性；环境因素（化学物质、辐射、营养等）可通过重塑染色质可及性及转录因子结合模式，参与疾病发病过程。 图 1：真核生物染色质可及性动态示意图 研究与结论：染色质可及性通过 “核小体重塑 - 表观修饰 - 转录因子结合 - 非编码 RNA 调控 - 染色质三维结构” 的多层级网络实现动态平衡，其调控机制具有显著的细胞类型特异性和上下文依赖性。这一复杂调控网络使细胞能灵活响应内外环境变化，为理解基因组功能的精准调控提供了核心框架，也为靶向染色质调控通路的疾病治疗提供了理论基础。 2. 染色质可及性在生理过程中的核心功能 染色质可及性在多种生理过程中发挥关键调控作用，是细胞命运决定与机体稳态维持的核心枢纽：在早期胚胎发育中，染色质可及性从 2 细胞阶段到囊胚阶段逐步增加，可及区域主要集中在启动子、CpG 岛及增强子，早期染色质可及性的预置状态对关键基因的后续高表达至关重要，H4K16ac 等组蛋白修饰通过维持染色质可及性，保障合子基因组激活；在器官发育中，心脏、肝脏、大脑、肺等不同器官的细胞通过组织特异性先锋转录因子重塑染色质可及性，如肝脏中 FoxA 家族调控肝特异性基因的染色质开放，心脏中 GATA4/5/6 家族通过染色质可及性调控心脏发育相关基因表达，大脑中染色质可及性图谱的动态变化参与神经细胞分化与功能维持；在组织再生中，肝脏、心脏等器官的损伤修复过程伴随染色质可及性的显著重塑，如肝脏再生中 Yamanaka 因子通过调控 TOP2A 表达改变染色质可及性，促进肝细胞去分化与增殖，斑马鱼心脏再生中 AP-1 结合基序的可及性增加驱动再生相关基因表达；在昼夜节律调控中，HNF4α 通过增强 BMAL1::CLOCK 复合物的染色质结合能力，重塑肝脏特异性昼夜转录组，而染色质可及性与昼夜节律基因表达相互调控；在衰老过程中，肝脏、骨髓间充质干细胞等细胞的染色质可及性呈现全局或局部变化，炎症相关基因区域可及性升高与衰老相关表型密切相关；此外，染色质可及性还参与性别相关表型差异的调控，如生长激素介导的雄性偏向性染色质开放调控肝脏基因表达。 图 2：染色质可及性研究关键发现时间线 研究与结论：染色质可及性在生理过程中呈现显著的时空动态特征，其变化通常先于基因转录改变，是细胞命运转换的核心驱动因素。不同生理过程中染色质可及性的特异性调控网络，不仅揭示了细胞分化、器官发育及稳态维持的分子机制，也为理解生理异常相关疾病的发病根源提供了全新视角。 3. 染色质可及性异常在疾病中的作用机制 染色质可及性的异常调控是多种疾病发病的核心机制之一，其在不同疾病中的特异性变化为疾病诊断与治疗提供了关键靶点：在肿瘤中，染色质可及性重塑参与肿瘤发生、增殖、转移、干细胞特性维持、免疫逃逸及化疗耐药等全过程，如肝癌中 ARID1A 缺失通过改变染色质可及性促进癌基因表达，结直肠癌中 SUV420H2 不足导致 H4K20me3 修饰减少，增强 Wnt 相关基因染色质可及性，乳腺癌中染色质可及性异质性与肿瘤亚型及治疗敏感性密切相关，且染色质可及性图谱可作为肿瘤风险位点筛选及预后评估的生物标志物；在心血管疾病中，扩张型心肌病中 LMNA 突变通过劫持 TEAD1 影响染色质可及性，心肌梗死中染色质可及性重塑参与心肌应激反应及修复过程，动脉粥样硬化中 ZEB2 缺失通过改变相关基因染色质可及性加速斑块形成；在肝脏疾病中，代谢相关脂肪性肝病（MASLD）、代谢相关脂肪性肝炎（MASH）中染色质可及性异常调控脂代谢及炎症相关基因，乙型肝炎病毒感染通过增强 cccDNA 染色质可及性促进病毒复制，肝纤维化中肝星状细胞激活伴随染色质可及性重塑；在神经系统疾病中，阿尔茨海默病（AD）患者大脑中 USF2 结合基序可及性异常，自闭症谱系障碍（ASD）中 CHD8 不足导致全局染色质可及性升高，成瘾相关疾病中 heroin 暴露改变纹状体 FYN 基因启动子可及性；在糖尿病中，1 型糖尿病中 BACH2 基因启动子可及性降低与自身免疫相关，2 型糖尿病中胰岛 β 细胞染色质可及性重塑影响胰岛素分泌相关基因表达；此外，染色质可及性异常还参与感染性疾病、骨质疏松、慢性肾病等多种疾病的发病过程。 图 3：染色质可及性检测的主要方法原理 研究与结论：染色质可及性异常是疾病发生发展的关键驱动因素，其在不同疾病中的特异性可及性图谱（位点、丰度、动态变化）不仅为疾病早期诊断、亚型分型及预后评估提供了潜在生物标志物，也为开发精准靶向治疗策略提供了明确靶点。尤其在肿瘤中，染色质可及性通过调控代谢重编程、免疫逃逸、基因组稳定性等核心过程，成为肿瘤精准治疗的理想枢纽靶点。 4. 基于染色质可及性调控的疾病治疗策略 针对染色质可及性调控网络的靶向治疗已成为疾病治疗的重要方向，目前开发的策略主要聚焦于核心调控因子的抑制剂开发：在核小体重塑复合物靶向方面，SWI/SNF 复合物抑制剂（如 ADAADi、BRM014、FHD-286）通过抑制 ATP 酶活性或溴结构域，改变染色质可及性以抑制肿瘤进展，NuRD 复合物抑制剂（如 ED2-AD101、HDAC1/2 抑制剂）通过调控核小体重塑及组蛋白去乙酰化，增强化疗敏感性，ISWI 复合物抑制剂（如 DCB29、C620-0696）及 INO80 复合物抑制剂（如 CB-6644、sorafenib）通过靶向核心亚基的 ATP 酶活性，抑制肿瘤细胞增殖；在 DNA 甲基化修饰靶向方面，DNMT 抑制剂（如阿扎胞苷、地西他滨）通过降低 DNA 甲基化，增强肿瘤抑制基因的染色质可及性，TET 酶抑制剂（如 bobcat339 hydrochloride）通过调控 DNA 去甲基化，逆转异常染色质可及性，且 DNMT 抑制剂与 HDAC 抑制剂、EZH2 抑制剂的联合使用可协同增强染色质可及性调控效果；在组蛋白修饰靶向方面，组蛋白乙酰转移酶抑制剂（如 GNE-781、A-485）通过抑制组蛋白酰化修饰，改变增强子染色质可及性，组蛋白去乙酰化酶抑制剂（如 SAHA、TSA、PCI-34051）通过增强组蛋白乙酰化，重塑染色质可及性以抑制肿瘤，组蛋白甲基转移酶抑制剂（如 EPZ-5676、GSK126）及去甲基化酶抑制剂（如 GSK-J4）通过调控组蛋白甲基化状态，改变关键基因的染色质可及性；在转录因子靶向方面，AR 抑制剂（如恩杂鲁胺）、Myc 抑制剂（如 MYCi975）、CDK9 抑制剂（如 AZD4573）等通过抑制转录因子与染色质的结合，重塑染色质可及性图谱，抑制疾病进展。 图 4：染色质可及性的主要调控因子示意图 研究与结论：染色质可及性调控网络的核心节点为疾病治疗提供了多维度靶点，针对核小体重塑复合物、表观修饰酶及转录因子的抑制剂在临床前或临床研究中已展现出显著潜力。通过合理设计联合治疗、序贯治疗及精准递送系统，可进一步提升治疗效果并降低脱靶毒性，但目前仍面临抑制剂特异性不足、生物标志物验证不充分、临床转化瓶颈等问题，需通过结构生物学、高通量筛选及多组学技术的融合应用，推动相关策略的临床转化。 结论与讨论 染色质可及性作为连接基因组功能与细胞微环境的核心枢纽，其动态调控机制的解析是表观遗传学领域的关键突破。本研究系统阐明了染色质可及性的多层级调控网络（核小体重塑、表观修饰、非编码 RNA、染色质三维结构等），明确了其在生理过程（胚胎发育、器官形成、组织再生等）中的时空动态特征，以及在疾病（肿瘤、心血管疾病、神经系统疾病等）中的异常调控机制，揭示了染色质可及性作为疾病诊断生物标志物及治疗靶点的核心价值。研究的创新价值在于首次全面整合了染色质可及性的调控机制与生理病理功能，打破了 “单一调控因子单一功能” 的传统认知，提出 “染色质可及性变化先于转录改变” 的核心观点，为疾病早期诊断与精准治疗提供了全新框架。 当前研究的局限性在于：缺乏细胞类型特异性抑制剂，现有抑制剂（如 2-BP）的广谱性导致脱靶毒性风险较高；染色质可及性与其他表观遗传机制（DNA 甲基化、组蛋白修饰）及转录调控的相互作用网络尚未完全阐明；临床样本中染色质可及性的直接检测受限于有创采样及技术复杂性，生物标志物的多队列验证不足；染色质三维结构与可及性变化的因果关系仍存在争议。 未来研究应聚焦三大方向：一是基于染色质调控因子的结构特征，开发高特异性抑制剂（如 zDHHC 酶选择性抑制剂、转录因子靶向 PROTACs），提升治疗精准性；二是利用微流控质谱、单细胞多组学、空间转录组学等新兴技术，开发可用于血清、灌洗液等无创样本检测的染色质可及性相关生物标志物，构建 “调控因子 - 染色质可及性 - 疾病表型” 的整合诊断框架；三是通过类器官、疾病模型等系统，解析染色质可及性调控在疾病不同阶段的动态变化，搭建临床前与临床研究的桥梁。尽管仍面临诸多挑战，但技术创新与机制研究的融合已使染色质可及性成为疾病研究的变革性前沿，基础科学家、临床医生及生物工程师的协同合作，将推动相关潜力转化为改善疾病患者预后的有效治疗手段。 往期回顾 琥珀酰化专题|Nature Genetics（2024IF：30.800，JCR Q1）解读：PD-L1 琥珀酰化修饰调控黑色素瘤抗肿瘤免疫应答 琥珀酰化专题|《Explor Target Antitumor Ther》的（DOI：10.37349/etat.2023.00196）解读：琥珀酰化：调控细胞信号与疾病发生的关键机制 琥珀酰化专题|《Neural Regeneration Research》（DOI：10.4103/1673-5374.382229）解读：琥珀酰化修饰：脑卒中治疗的潜在靶向机制 琥珀酰化专题|《Frontiers in Neurology》（10.3389/fneur.2025.1678595）解读：赖赖氨酸琥珀酰化：神经退行性疾病的代谢 - 表观遗传核心 琥珀酰化专题|《Redox Biology》（2025年，88:103932）解读：赖氨酸琥珀酰化作为心血管疾病的代谢开关：机制见解与治疗前景 关于我们 安提海拉生物科技（厦门）有限公司成立于2015年4月。公司集研究、开发、销售生物产品为一体，是一家新兴的高新技术企业。公司依托现代科学技术，致力于提供分子生物学技术服务与相关产品，包括基因过表达与抑制（如多种病毒颗粒及Talen，crispr系统），超纯细胞因子、生长因子等蛋白产品以及其他分子生物学、细胞生物学服务。我们的目标是通过为科研院所及生物制药公司提供高品质的服务和产品，从而促进现代生物医学及制药行业的发展     长按识别二维码      关注微信公众号            关注视频号            全文链接：www.nature.com/sigtrans