Miltefosine attenuates silicosis involving inhibiting the Akt/mTOR signaling pathway
- Eur J Pharmacol. 2026 Jul 10:1029:178931. doi: 10.1016/j.ejphar.2026.178931.
- 1. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Geriatric Respiratory Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- 2. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
- 3. Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
- 4. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, 430030, China.
- 5. Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
- 6. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China. Electronic address: [email protected].
- 7. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China. Electronic address: [email protected].
- 8. Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China. Electronic address: [email protected].
Silicosis is an irreversible respiratory condition resulting from exposure to respirable crystalline silica. Presently, the prevalence of silicosis remains significant, with treatment options being notably limited. Miltefosine, an inhibitor of phosphatidylcholine synthesis, has been found to possess both anti-inflammatory properties and inhibitory effects on immune cell infiltration in the airways. The present study evaluated the therapeutic potential of miltefosine in silica-associated pulmonary fibrosis. We established mouse models via airway administration of silicon dioxide (SiO2) (200 mg/kg). Different type of pulmonary fibrosis (PF) model including bleomycin (BLM) and Fluorescein Isothiocyanate (FITC) were then utilized to examine the therapeutic effect of Miltefosine. Oral miltefosine exhibits significant therapeutic efficacy against pulmonary fibrosis induced by SiO2, as well as Other etiologies such as BLM and FITC. This efficacy is evidenced by significant reductions in fibrotic markers and pathological staining characteristics post-treatment, paralleling the antifibrotic effects observed with pirfenidone. In cellular experiments, primary fibroblasts from idiopathic pulmonary fibrosis (IPF) patients and healthy controls were utilized for in vitro therapeutic evaluation and mechanistic exploration. Miltefosine was found to attenuate fibrosis progression by inhibiting fibroblast activation, proliferation, and migration capabilities, while promoting Apoptosis. Mechanistically, miltefosine exerts its effects by inhibiting Akt activation, which in turn prevents mTOR phosphorylation. Additionally, human precision-cut lung slices (hPCLS) was employed to evaluate the efficacy of miltefosine in treating pulmonary fibrosis induced by a cocktail of agents, and miltefosine significantly reduced its Collagen deposition. Our results imply that miltefosine can alleviate SiO2-induced pulmonary fibrosis in murine models and attenuate fibrosis progression in hPCLS by inhibiting fibroblast activation through the suppression of Akt activation and mTOR phosphorylation.