Homoharringtonine exerts anti-silicosis effects by inhibiting the CCR1 and PI3K/AKT signaling pathways in lung fibroblasts

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.

Keywords

silicosis / homoharringtonine / lung fibroblast / PI3K/AKT/mTOR signaling pathway / CCR1

Fundings

This project was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82473601 to Y.L., 82404234 to W.S., and 82073518 to C.N.) and the Foundation of Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning (Grant No. 2022-2023ZYBKF04 to C.N.).

Acknowledgments

None.

References

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