卵巢癌是常见妇科肿瘤中预后较差的疾病，由于早期症状隐匿，绝大多数患者至晚期才可确诊，广泛的腹腔转移为其特征，导致治疗棘手。目前，手术治疗联合以铂类为基础的化疗为卵巢癌的标准治疗方案，但最终不可避免发展为耐药性卵巢癌，影响治疗疗效及预后。化疗耐药和腹腔多发性转移是卵巢癌临床面临的主要问题，因此，寻找新的药物或新的治疗策略对于改善卵巢癌化疗敏感性至关重要。

肿瘤是一种系统性的全身疾病，肿瘤细胞与肿瘤微环境（Tumor microenvironment，TME）中的基质细胞、免疫细胞等细胞成分，及细胞外基质（Extracellular Matrix，ECM）与血管系统构成复杂而动态的网络，通过协同的交互作用介导肿瘤进展，复发转移及治疗耐药。肿瘤的标志特征之一为ECM重塑，以肿瘤相关成纤维细胞（Tumor-associated fibroblast，CAFs）和肿瘤相关巨噬细胞（Cancer-associated macrophages，TAMs）为主的基质细胞，通过分泌细胞因子和趋化因子等非细胞组分，改变ECM结构和硬度，重塑ECM，导致纤维结缔组织增生以及组织纤维化的形成；ECM过度沉积形成致密的网络结构，构成阻碍药物渗透及免疫细胞浸润的物理屏障，进而促进肿瘤细胞生长。靶向ECM可能是肿瘤化疗及免疫治疗增敏潜在的治疗策略，然而由于肿瘤细胞与肿瘤微环境动态的协同互作、肿瘤的异质性与适应性，如何更精准的靶向特定ECM组分及筛选敏感群体是亟待解决的问题。

蛋白组学分析较为系统地解析了ECM重塑的复杂性和动态性，揭示22个ECM基因signature (Matrix index，基质指数)可以用于评价卵巢癌与其它 12 种原发性实体瘤组织的软硬度和患者的预后。在本文中，我们发现Matrix index可以预测卵巢癌的化疗反应和预后，利用卵巢癌单细胞RNA-seq (scRNA-seq)数据分析发现，富含胶原的致密ECM比松散的ECM含有更多的M2型TAMs，推测其可能与免疫抑制微环境的形成相关；为了鉴定与卵巢癌耐药相关的核心ECM组分，我们基于化疗耐药相关基因、基质指数及纤维化相关基因的交互分析及系列实验，确定I型胶原α1链（COL1A1）与卵巢癌耐药和不良预后相关，提示COL1A1可能是卵巢癌一个潜在的治疗靶点；为了探寻靶向COL1A1的小分子化合物，我们利用中医药百科全书数据库（The Encyclopedia of Traditional Chinese Medicine，ETCM）鉴定了常山酮（Halofuginone，HF），一种具有临床活性的常山碱衍生物，为靶向COL1A1的天然化合物。在分子机制上，常山酮通过mTOR-eIF2α-ATF4轴抑制CAFs分泌COL1A1；体内动物模型揭示常山酮可显著增强卵巢癌细胞的铂类敏感性；常山酮通过抑制胶原沉积，促进M2-M1巨噬细胞极化及增加CD8+ T细胞浸润，进而增强化疗敏感性。

本研究聚焦于ECM介导的卵巢癌耐药，较为系统的解析了ECM致密程度与卵巢癌耐药及预后相关；靶向细胞外基质蛋白COL1A1可以增强卵巢癌铂敏感性，有望为卵巢癌耐药患者提供一种新的治疗策略。

卵巢癌是常见妇科肿瘤中预后较差的疾病，由于早期症状隐匿，绝大多数患者至晚期才可确诊，广泛的腹腔转移为其特征，导致治疗棘手。目前，手术治疗联合以铂类为基础的化疗为卵巢癌的标准治疗方案，但最终不可避免发展为耐药性卵巢癌，影响治疗疗效及预后。化疗耐药和腹腔多发性转移是卵巢癌临床面临的主要问题，因此，寻找新的药物或新的治疗策略对于改善卵巢癌化疗敏感性至关重要。

肿瘤是一种系统性的全身疾病，肿瘤细胞与肿瘤微环境（Tumor microenvironment，TME）中的基质细胞、免疫细胞等细胞成分，及细胞外基质（Extracellular Matrix，ECM）与血管系统构成复杂而动态的网络，通过协同的交互作用介导肿瘤进展，复发转移及治疗耐药。肿瘤的标志特征之一为ECM重塑，以肿瘤相关成纤维细胞（Tumor-associated fibroblast，CAFs）和肿瘤相关巨噬细胞（Cancer-associated macrophages，TAMs）为主的基质细胞，通过分泌细胞因子和趋化因子等非细胞组分，改变ECM结构和硬度，重塑ECM，导致纤维结缔组织增生以及组织纤维化的形成；ECM过度沉积形成致密的网络结构，构成阻碍药物渗透及免疫细胞浸润的物理屏障，进而促进肿瘤细胞生长。靶向ECM可能是肿瘤化疗及免疫治疗增敏潜在的治疗策略，然而由于肿瘤细胞与肿瘤微环境动态的协同互作、肿瘤的异质性与适应性，如何更精准的靶向特定ECM组分及筛选敏感群体是亟待解决的问题。

蛋白组学分析较为系统地解析了ECM重塑的复杂性和动态性，揭示22个ECM基因signature (Matrix index，基质指数)可以用于评价卵巢癌与其它 12 种原发性实体瘤组织的软硬度和患者的预后。在本文中，我们发现Matrix index可以预测卵巢癌的化疗反应和预后，利用卵巢癌单细胞RNA-seq (scRNA-seq)数据分析发现，富含胶原的致密ECM比松散的ECM含有更多的M2型TAMs，推测其可能与免疫抑制微环境的形成相关；为了鉴定与卵巢癌耐药相关的核心ECM组分，我们基于化疗耐药相关基因、基质指数及纤维化相关基因的交互分析及系列实验，确定I型胶原α1链（COL1A1）与卵巢癌耐药和不良预后相关，提示COL1A1可能是卵巢癌一个潜在的治疗靶点；为了探寻靶向COL1A1的小分子化合物，我们利用中医药百科全书数据库（The Encyclopedia of Traditional Chinese Medicine，ETCM）鉴定了常山酮（Halofuginone，HF），一种具有临床活性的常山碱衍生物，为靶向COL1A1的天然化合物。在分子机制上，常山酮通过mTOR-eIF2α-ATF4轴抑制CAFs分泌COL1A1；体内动物模型揭示常山酮可显著增强卵巢癌细胞的铂类敏感性；常山酮通过抑制胶原沉积，促进M2-M1巨噬细胞极化及增加CD8+ T细胞浸润，进而增强化疗敏感性。

本研究聚焦于ECM介导的卵巢癌耐药，较为系统的解析了ECM致密程度与卵巢癌耐药及预后相关；靶向细胞外基质蛋白COL1A1可以增强卵巢癌铂敏感性，有望为卵巢癌耐药患者提供一种新的治疗策略。

Ovarian cancer has one of common gynecologic malignancies with poor prognosis. Most of patients are diagnosed at an advanced stage with the extensive metastasis due to the lack of symptoms in the early stages making treatment particularly challenging. Currently, surgical treatment combined with platinum-based chemotherapy is the standard treatment, however, chemoresistance is inevitable, causing the poor therapeutic efficacy and prognosis. Chemoresistance and multifocal peritoneal metastases remain major clinical challenges in ovarian cancer, therefore, highlighting the urgent need for novel drugs or therapeutic strategies to improve chemosensitivity.

Cancer is a systemic disease characterized by a complex and dynamic network formed through the interaction between cancer cell and the tumor microenvironment (TME), which includes stromal cells, immune cells, the extracellular matrix (ECM), and the vascular system. These components interact synergistically to drive tumor progression, recurrence, metastasis, and therapeutic resistance. ECM remodeling is a hallmark of cancer, stromal cells such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (TAMs) secrete cytokines and chemokines that alter the composition and stiffness of the ECM, leading to ECM remodeling, resulting in fibrous connective tissue proliferation and fibrosis. Excessive ECM deposition in tumors forms a dense network that acts as a physical barrier, impeding drug penetration and immune cell infiltration, thereby facilitating tumor growth. Previous studies have shown that targeting ECM represents a promising strategy to improve the efficacy of chemotherapy and immunotherapy. However, due to the dynamic interplay between cancer cells and TME, as well as tumor heterogeneity and adaptability, precisely targeting of specific ECM components and screening for responsive patients remain major challenges.

Proteomic analysis has systematically elucidated the complexity and dynamic of ECM remodeling, identifying a 22-gene ECM signature (termed: Matrix index) that can assess tissue stiffness and predict patient prognosis in ovarian cancer and 12 other primary solid tumors. In this study, we found that Matrix index predicts chemotherapy response and prognosis in ovarian cancer. The collagen rich in dense ECM harbor more M2 TAMs compared to the loose ECM based on single-cell RNA sequencing (scRNA-seq), suggesting a potential role in reshaping an immunosuppressive microenvironment. Subsequently, we performed an integrative analysis based on 22 matrisome genes, fibrosis-related genes, and DEGs in Matrix^H/Matrix^L in TCGA and GSE156699 datasets, and identified COL1A1. Collagen type I alpha 1 chain (COL1A1), the major component of ECM mediated chemoresistance, highlighting its potential role of therapeutic target. Furthermore, we screened the potential natural com pounds of targeting COL1A1 using ETCM (http://www.tcmip.cn/ETCM), and found that antifebrile dichroa, a natural compound, emerged as a promising candidate. Mechanistically, HF inhibits COL1A1 production via the mTOR-eIF2α-ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2-M1 macrophage polarization to enhance chemosensitivity.

Our study focuses on ECM-mediated chemoresistance in ovarian cancer and systematically elucidates the association between ECM density and both resistance and prognosis. targeting COL1A1 may enhance platinum sensitivity in ovarian cancer. Overall，the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.