Abstract: Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace. It has a complex pathogenesis and currently lacks effective treatments. Homoharringtonine (HHT) is a natural compound approved for the treatment of acute myeloid leukemia, but its effects on silicosis remain unclear. In the present study, we constructed a mouse model of silica (SiO₂)-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT. The results showed that HHT significantly attenuated the progression of SiO₂-induced pulmonary fibrosis in mice. We then used MRC-5, a human lung fibroblast cell line, to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells. Mechanistically, these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein. Furthermore, HHT exhibited favorable biocompatibility in vivo, and its preventive and therapeutic effects were validated in SiO₂-treated mice. Collectively, the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/mTOR signaling pathway, highlighting it as a promising candidate for clinical translation for silicosis treatment.