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纤维化是机体对组织损伤的一种修复失控，表现为胶原蛋白等细胞外基质的病理性堆积，最终导致器官硬化、功能丧失甚至死亡。从肺部到肝脏、从心脏到肾脏，纤维化几乎可发生于所有器官系统，构成了沉重的全球健康负担。然而，针对纤维化的有效药物研发长期面临瓶颈，现有疗法多局限于延缓而非逆转疾病进程。本文基于多组学技术带来的新认知，从细胞异质性、微环境重塑和信号网络调控的角度，深入解读了器官特异性纤维化机制，并展望了包括CAR-T疗法、人工智能辅助药物发现等在内的前沿治疗策略。 一、纤维化的核心概念 定义：纤维化是组织修复失调导致的细胞外基质（ECM）过度沉积，最终导致器官结构破坏和功能衰竭。 影响器官：肺、心、肝、肾等几乎所有器官系统。 全球负担：约25%的全球人口受纤维化相关疾病影响。 图 1：器官纤维化的病因和机制概述。正常器官在暴露于各种致病因素（如环境颗粒、慢性感染、辐射、高血压和糖尿病）时可能会发生纤维化。在损伤的响应中，细胞成分会发生信号通路激活、表观遗传重塑和DNA损伤等变化。这些变化会导致细胞事件，如细胞凋亡、坏死、代谢重编程、衰老和上皮-间质转化（EMT），从而改变组织微环境，包括细胞间相互作用和促纤维生成效应物（如细胞因子、代谢物和细胞外基质成分）的产生，从而调节器官纤维化。二、历史里程碑 1685年：首次描述肝硬化。 19世纪：发现肺、心、肾纤维化。 20世纪：发现胶原蛋白类型、肌成纤维细胞、TGF-β、EMT/EndoMT等关键机制。 近年： 2011–2014年：FDA批准吡非尼酮和尼达尼布用于IPF。 2024年：Resmetirom获批用于MASH相关肝纤维化。 2025年：Semaglutide获批用于MASH伴肝纤维化。 AI辅助药物设计（如Rentosertib）进入临床试验。 图2：器官纤维化里程碑时间线。EMT上皮-间充质转化，TGF-β转化生长因子-β，HSC肝星状细胞，EndoMT内皮-间充质转化，MMT巨噬细胞-间充质转化，IPF特发性肺纤维化，BM-MSCs骨髓来源的间充质干细胞，CAR-T嵌合抗原受体T细胞，MASH代谢性功能障碍相关脂肪性肝炎，AI人工智能。三、器官特异性纤维化机制1. 肺纤维化（IPF为代表） 关键细胞：AT2细胞（肺泡上皮）、成纤维细胞、内皮细胞、免疫细胞。 机制： AT2细胞异常分化、衰老、EMT。 成纤维细胞激活为肌成纤维细胞（CTHRC1+）。 内皮细胞功能障碍、EndoMT、分泌促纤维化因子。 免疫细胞（如SPP1+巨噬细胞）驱动纤维化。 图 3：肺纤维化的机制及细胞相互作用。2. 心脏纤维化 类型：反应性间质纤维化、浸润性血管周围纤维化、替代性纤维化。 关键细胞： 心肌细胞：分泌miRNA、SASP因子、ROS。 成纤维细胞：POSTN+、RUNX1+等亚群。 内皮细胞：EndoMT、机械感应失调。 免疫细胞：SPP1+巨噬细胞、T细胞等。 图4：心脏纤维化的机制和细胞相互作用。3. 肝纤维化 关键细胞： 肝细胞：释放DAMPs、LECT2、IL-11等激活HSC。 肝星状细胞（HSC）：主要ECM来源，具空间异质性。 肝窦内皮细胞（LSEC）：毛细血管化、分泌促纤维化因子。 免疫细胞：TREM2+巨噬细胞、中性粒细胞等。 图5：肝纤维化的机制和细胞相互作用。4. 肾纤维化 关键细胞： 肾小管上皮细胞：衰老、铁死亡、释放DAMPs。 成纤维细胞/周细胞：主要来源为PDGFRα/β+细胞。 内皮细胞：EndoMT、血管稀疏。 免疫细胞：SPP1+巨噬细胞、ILC3、嗜碱性粒细胞等。 图6：肾纤维化的机制和细胞相互作用。四、关键信号通路 图7：纤维化过程中涉及的关键信号通路的示意图。 通路 作用TGF-β 核心促纤维化通路，激活SMAD与非SMAD通路Wnt 促HSC/成纤维细胞激活MAPK JNK/ERK/p38促进增殖与ECM沉积Hippo/YAP 调控细胞增殖与转分化JAK/STAT 炎症与纤维化桥接PI3K/AKT 细胞存活、代谢重编程PPAR 抗纤维化靶点（如PPARγ）Notch 调控细胞命运与EMTcGAS-STING DNA损伤诱导炎症与衰老Rho/ROCK 细胞收缩、ECM沉积PDGF/FGF/VEGF 细胞增殖与血管重塑ER stress 诱导凋亡、EMT、炎症五、抗纤维化药物与临床试验已上市药物： 吡非尼酮（IPF） 尼达尼布（IPF） Resmetirom（MASH肝纤维化） Semaglutide（MASH肝纤维化）在研药物（按靶点分类）： TGF-β：Fresolimumab、LY2382770、TRK-250 Wnt：PRI-724、Niclosamide JAK：Ruxolitinib、Baricitinib PPAR：Lanifibranor、Elafibranor Integrin：PLN-74809、IDL-2965 FGF21 analogs：Pegozafermin、Efruxifermin RTK抑制剂：Nintedanib、Anlotinib ER stress：4-PBA、KIRAs六、未来方向 多组学整合： 单细胞+空间转录组+代谢组+蛋白组 识别跨器官共享的促纤维化细胞亚群（如SPP1+巨噬细胞、FAP+成纤维细胞） CAR-T/ CAR-M疗法： 靶向FAP、uPAR、PDGFRβ等 体内瞬时CAR-T（LNP-mRNA）具前景 人工智能（AI）应用： 辅助病理诊断（如MASH评分） 药物靶点发现（如TNIK抑制剂INS018_055） 药物重定位（如lubiprostone）结论 纤维化是多种慢性疾病的共同终末通路。 各器官虽有特异性机制，但共享关键细胞类型与信号通路。 未来治疗需结合多组学、AI、细胞治疗等多维度手段，实现精准干预。 左下角“阅读原文”可查看原文献；设置⭐星标，不错过精彩推文 向有意向客户提试样/试用服务 欢迎咨询交流 长按上方二维码可添加微信； 也可直接拨打153-3688-1895 主要提供两类设备 一类是细胞刺激力学加载(国产仪器可试用30天)： 细胞牵张刺激系统 细胞静水压缩系统 细胞流体剪切系统 细胞电刺激系统 一类是测量弹性/粘弹性仪器 1. 生物力学试验机 2. 生物材料双轴力学测试系统 3. 生物纳米压痕仪 4. 微球压缩测试系统

PLN-101095 Phase 1 data showed deep and durable ongoing responses in checkpoint inhibitor refractory solid tumors PLN-101095 accelerated development plan underway with initiation of Phase 1b indication expansion trial SOUTH SAN FRANCISCO, Calif., March 11, 2026 (GLOBE NEWSWIRE) -- Pliant Therapeutics, Inc. (Nasdaq: PLRX), a clinical-stage biotechnology company focused on the discovery and development of integrin-based therapeutics, today provided a corporate update and reported fourth quarter 2025 financial results. “We ended 2025 with encouraging data from our lead oncology program in ICI-refractory patients, an area of unmet medical need, that informed the initiation of our accelerated development plan for PLN-101095,” said Bernard Coulie, M.D., Ph.D., President and Chief Executive Officer of Pliant. “In addition to oncology and the early-stage pipeline programs emerging from Pliant's proprietary integrin platform, we continue to assess opportunities to expand our clinical-stage pipeline that leverage our areas of expertise and align with creating shareholder value.” Fourth Quarter and Recent Developments Oncology Program PLN-101095 is an oral, small molecule, dual selective inhibitor of αvβ8 and αvβ1 integrins designed to overcome checkpoint resistance by blocking TGF-β activation in the tumor microenvironment. Pliant is currently conducting a Phase 1a/1b open-label, dose-escalation and indication expansion trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary evidence of antitumor activity of PLN-101095, as monotherapy and in combination with pembrolizumab , in patients with immune checkpoint inhibitor (ICI)-refractory advanced or metastatic solid tumors. Data from the Phase 1 trial of PLN-101095 showed deep and durable ongoing responses. In December, the Company announced positive data showing that, in a heavily pretreated patient population, PLN-101095 demonstrated anti-tumor activity in combination with pembrolizumab , an FDA-approved ICI. Four responders were observed consisting of one confirmed complete response and three partial responses (two confirmed, one unconfirmed) out of the 10 secondary ICI refractory patients. These clinical responses were observed in patients with cholangiocarcinoma, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer (NSCLC). Notably, all responding patients showed large increases in plasma interferon gamma (IFN-γ) after 14 days of monotherapy with PLN-101095 prior to the addition of pembrolizumab . No non-responders showed meaningful increases in plasma IFN- γ. PLN-101095 was generally well tolerated across all doses tested. IFN-γ is known to play a multifaceted role in modulating anti-tumor immunity, with increased tumor expression levels having previously been linked with better outcomes from immune checkpoint blockade. Accelerated development plan of PLN-101095 underway with initiation of Phase 1b indication expansion trial. Based on the encouraging response data and supportive IFN- γ biomarker data from the Phase 1 trial, the Company is advancing an accelerated clinical development plan of PLN-101095 and has initiated a Phase 1b indication expansion trial. The Phase 1b open-label, single dose trial will enroll three cohorts of patients including NSCLC, clear cell renal cell carcinoma and tumors with high tumor mutational burden. Tumor selection was based on data from the Phase 1 trial, as well as strong mechanistic rationale for integrin inhibition. Patients will be treated for 14 days with PLN-101095 dosed at 1,000 mg twice daily as monotherapy, after which pembrolizumab will be added as combination therapy. Study start activities for this trial are underway with first patient enrollment anticipated in second quarter. Interim data is expected in 2027. PLN-101095 Phase 1 data accepted for presentation at AACR Annual Meeting 2026. Data from the Phase 1 trial of PLN-101095 will be the subject of a poster presentation and an oral presentation as part of the Clinical Trials Minisymposium at the upcoming American Association of Cancer Research (AACR) conference to be held April 17-22, 2026, in San Diego, California. Integrin-Targeted Delivery Platform Utilizing cell-specific integrin receptors, Pliant has developed a platform to deliver drug payloads, including siRNAs, to selective tissue types. Current programs are focused on delivering siRNAs to skeletal muscle cells and other tissues. The Company believes this integrin-targeting delivery platform has the potential for broad applicability across multiple disease areas utilizing a variety of drug payloads. Corporate Highlights Appointment of Minnie Kuo as Chief Operating Officer. Ms. Kuo joined Pliant in September 2023 as Chief Development Officer, bringing more than 20 years of multinational clinical development experience across various therapeutic areas. In this expanded role, Ms. Kuo bridges Pliant’s science and operations with oversight of clinical operations, early development, program management, regulatory affairs and compliance. INTEGRIS-PSC results published in the Journal of Hepatology . The manuscript, “ Phase II INTEGRIS-PSC trial of bexotegrast, an αvβ6 and αvβ1 integrin inhibitor, in primary sclerosing cholangitis ”, appears in the January 2026 issue of the Journal of Hepatology . Fourth Quarter 2025 Financial Results Research and development expenses were $15.6 million as compared to $38.8 million for the prior-year quarter. The decrease was primarily driven by the discontinuation of BEACON-IPF. General and administrative expenses were $8.0 million as compared to $14.5 million for the prior-year quarter. The decrease was primarily due to lower personnel-related costs resulting from the strategic restructuring of our workforce. Net loss was $23.6 million as compared to $49.7 million for the prior-year quarter. The decrease was primarily attributable to the discontinuation of BEACON-IPF coupled with the decrease in personnel-related costs resulting from the strategic restructuring of our workforce. As of December 31, 2025, the Company had cash, cash equivalents and short-term investments of $192.4 million which the Company expects to be sufficient to fund operations into the second half of 2028. About Pliant Therapeutics, Inc. Pliant Therapeutics is a clinical-stage biopharmaceutical company focused on the discovery and development of integrin-based therapeutics. The Company’s lead program is PLN-101095, a small molecule, dual-selective inhibitor of αvß8 and αvß1 integrins, that is being developed for the treatment of solid tumors. Pliant’s early-stage platform includes preclinical research focused on tissue-specific delivery and internalization of drug payloads utilizing integrin receptor-binding molecules. For additional information, please visit: . Follow us on social media X , LinkedIn and Facebook . Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "anticipate," "estimate," "intend," and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These express or implied statements include those regarding PLN-101095's development plan, including anticipated timing of data from our ongoing Phase 1 trial and our Phase 1b indication expansion trial, expansion of our clinical-stage pipeline and creation of shareholder value, and the potential of our integrin-targeted delivery platform, among others. Because such statements deal with future events and are based on our current expectations, they are subject to various risks and uncertainties and our actual results, performance or achievements could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including those related to the clinical development of our product candidates, including any delays in our ongoing or planned preclinical or clinical trials, or interactions with regulators, as well as the impact of current macroeconomic, geopolitical and marketplace conditions on our business, operations, clinical supply and plans, our reliance on single-source third parties located in foreign jurisdictions, including China, for critical aspects of our development operations, the risks inherent in the drug development process, the risks regarding the accuracy of our estimates of expenses and timing of development, our capital requirements and the need for additional financing, and our ability to obtain and maintain intellectual property protection for our product candidates. These and additional risks are discussed in the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" in our Annual Report on Form 10-K for the period ended December 31, 2025 which we are filing with the SEC today, available on the SEC's website at Unless otherwise noted, Pliant is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise. Investor and Media Contact: Christopher Keenan Vice President, Investor Relations and Corporate Communications Pliant Therapeutics, Inc. ir@pliantrx.com Pliant Therapeutics, Inc. Condensed Statements of Operations (Unaudited) (In thousands, except number of shares and per share amounts) Three Months Ended December 31, Twelve Months Ended December 31, 2025 2024 2025 2024 Operating expenses: Research and development $ (15,585 ) $ (38,793 ) $ (109,157 ) $ (169,310 ) General and administrative (7,992 ) (14,527 ) (47,216 ) (59,055 ) Total operating expenses (23,577 ) (53,320 ) (156,373 ) (228,365 ) Loss from operations (23,577 ) (53,320 ) (156,373 ) (228,365 ) Interest and other income (expense), net 1,964 4,422 11,416 21,085 Interest expense (136 ) (834 ) (2,559 ) (3,024 ) Loss on extinguishment of debt (1,828 ) — (1,828 ) — Net loss $ (23,577 ) $ (49,732 ) $ (149,344 ) $ (210,304 ) Net loss per share - basic and diluted $ (0.38 ) $ (0.82 ) $ (2.43 ) $ (3.47 ) Shares used in computing net loss per share - basic and diluted 61,449,290 60,854,322 61,366,887 60,538,639 Pliant Therapeutics, Inc. Condensed Balance Sheets (Unaudited) (In thousands) December 31, 2025 December 31, 2024 Assets Current assets Cash and cash equivalents $ 45,445 $ 71,188 Short-term investments 145,499 284,536 Prepaid expenses and other current assets 4,464 6,540 Property and equipment held for sale 1,040 — Total current assets 196,448 362,264 Property and equipment, net 2,940 5,525 Operating lease right-of-use assets 23,966 27,243 Restricted cash 1,482 1,482 Other non-current assets 392 435 Total assets $ 225,228 $ 396,949 Liabilities and stockholders’ equity Current liabilities Accounts payable $ 480 $ 5,960 Accrued research and development 4,804 14,363 Accrued liabilities 9,634 12,353 Lease liabilities, current 1,447 542 Total current liabilities 16,365 33,218 Lease liabilities, non-current 27,658 29,439 Long-term debt — 30,211 Total liabilities 44,023 92,868 Commitments and Contingencies Stockholders’ equity Preferred stock — — Common stock 6 6 Additional paid-in capital 1,040,610 1,013,806 Accumulated deficit (859,396 ) (710,052 ) Accumulated other comprehensive (loss) gain (15 ) 321 Total stockholders’ equity 181,205 304,081 Total liabilities and stockholders’ equity $ 225,228 $ 396,949