Low-intensity stimulation drives macrophage efferocytosis via ACSL4 lipid remodeling and CCL9-CCR1 signaling for tendon-bone healing
- Juncheng Yao
- Yuhao Wu
- Xuan Wang
- Jiexin Zhang
- Yan Shao
- Huabin Chen
- Haiyan Zhang
- Haobin Li
- Jianying Pan
- Yitao Zhao
- Daozhang Cai
- Denghui Xie
- Chun Zeng
2026-07-10
The mechanisms underlying exercise rehabilitation–induced tendon-bone healing remain unclear. Using a mouse model of anterior cruciate ligament reconstruction, we found that low-intensity mechanical stimulation promoted macrophage M2 polarization, phagocytosis, and efferocytosis at the tendon-bone interface via acyl-CoA synthetase long-chain family member 4 (ACSL4)–mediated lipid metabolism reprogramming. Acsl4 silencing reduced fatty acid oxidation and efferocytosis, impairing exercise rehabilitation–induced tendon-bone healing. Notably, the CCL9-CCR1 axis contributed to bone marrow stromal cell homing following macrophage efferocytosis. In addition, engineered CCL9-expressing exosomes accelerated tendon-bone repair.