PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast crosstalk and EndMT

作者：Zejin Zhang, Zhenzhen Yan, Tao Yuan, Xiaona Zhao, Minghui Wang, Guoqing Liu, Lijun Gan, Wei Qin · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2025.1549487 · 被引用次数：5 · 研究领域：Cardiac Fibrosis and Remodeling、Congenital heart defects research、Cancer Immunotherapy and Biomarkers

Introduction: Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood. Methods: C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays. Results: We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does...