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However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22\u2010gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen\u2010rich ECM secreted by CAFs harbors more M2 tumor\u2010associated macrophages (TAMs) than the looser ECM based on single cell RNA\u2010seq (scRNA\u2010seq) of ovarian cancer, suggesting the promising approach of targeting collagen to remodel ECM. An integrated analysis identifies collagen type I alpha 1 chain (COL1A1) as a major component of the ECM that contributes to chemoresistance and poor prognosis, highlighting its potential as a therapeutic target. Halofuginone (HF), a clinically active derivative of febrifugine, is identified as a COL1A1\u2010targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). Mechanistically, HF inhibits COL1A1 production via the mTOR\u2010eIF2\u03b1\u2010ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2\u2010M1 macrophage polarization to enhance chemosensitivity. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.<\/jats:p>","DOI":"10.1002\/advs.202416523","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T17:56:53Z","timestamp":1742925413000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Halofuginone Disrupted Collagen Deposition via mTOR\u2010eIF2\u03b1\u2010ATF4 Axis to Enhance Chemosensitivity in Ovarian Cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Wenxin","family":"Li","sequence":"first","affiliation":[{"name":"State Key Lab of Molecular Oncology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  17 Nanli Panjiayuan, Chaoyang District Beijing 100021 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