Halofuginone Disrupted Collagen Deposition via mTOR‐eIF2α‐ATF4 Axis to Enhance Chemosensitivity in Ovarian Cancer

Abstract The interplay between cancer‐associated fibroblasts (CAFs) and extracellular matrix (ECM) mediates progress, metastasis, and therapy resistance. However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22‐gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen‐rich ECM secreted by CAFs harbors more M2 tumor‐associated macrophages (TAMs) than the looser ECM based on single cell RNA‐seq (scRNA‐seq) 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‐targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). 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. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.