SPP1 promotes fatty acid synthesis in macrophages to drive silicosis

  • Cell Signal. 2026 Oct:146:112693. doi: 10.1016/j.cellsig.2026.112693.
Xinchun Chen  1 ,  Tian Li  2 ,  Jiashuo Wang  1 ,  Xinyue Yang  1 ,  Xinru Sun  1 ,  Fuyu Jin  1 ,  Yaqian Li  3 ,  Na Mao  1 ,  Xuemin Gao  1 ,  Zhongqiu Wei  4 ,  Ying Zhu  1 ,  Dingjie Xu  3 ,  Jinlong Li  1 ,  Ling Xue  1 ,  Fang Yang  5 ,  Hong Xu  6 ,  Wenchen Cai  7
Affiliations
  • 1. School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China.
  • 2. College of Nursing and Rehabilitation, Hebei Key Laboratory of Rehabilitation Engineering and Regenerative Medicine, North China University of Science and Technology, Tangshan 063210, China.
  • 3. Traditional Chinese Medicine College, North China University of Science and Technology, Tangshan, Hebei 063210, China.
  • 4. School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, China.
  • 5. School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China. Electronic address: [email protected].
  • 6. Health Science Center, North China University of Science and Technology, Tangshan, Hebei 063210, China. Electronic address: [email protected].
  • 7. School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China. Electronic address: [email protected].
PMID: 42349708 DOI: 10.1016/j.cellsig.2026.112693
Abstract

Osteopontin (SPP1) plays a critical role in the initiation and progression of silicosis, but whether macrophage-derived SPP1 regulates lipid metabolism during silicosis remains unclear. In this study, RNA Sequencing of lung tissues from silicotic mice and silica-stimulated alveolar macrophages identified Spp1 as a differentially expressed gene, and pathway enrichment analysis revealed significant enrichment of lipid metabolism-related signaling pathways. Using in vivo and in vitro models of silicosis, we assessed changes in SPP1 expression and key fatty acid synthesis markers. Silica stimulation increased SPP1 expression, induced lipid droplet formation, and upregulated fatty acid synthesis-related proteins. Subsequent in vitro experiments, including Spp1 knockdown, overexpression, and recombinant protein treatment, demonstrated that Spp1 knockdown effectively suppressed silica-induced lipid droplet formation and fatty acid synthesis. Mechanistically, SPP1 activated the fatty acid synthesis pathway by binding to its receptor CD44, thereby promoting SREBP-1 processing and nuclear translocation. Notably, CD44 silencing abrogated SPP1-induced lipid droplet formation, the upregulation of fatty acid synthesis Enzymes, and the production of pro-inflammatory cytokines (TNF-α and IL-6). Moreover, macrophage-specific knockout of Spp1 significantly alleviated pulmonary fibrosis, improved lung function, and inhibited the fatty acid synthesis pathway in vivo. Collectively, this study elucidates a novel mechanism by which SPP1 regulates macrophage fatty acid metabolism through the CD44/SREBP-1 axis, providing a mechanistic basis for targeting SPP1 in silicosis treatment.

Keywords
CD44; Fatty acid synthesis; Macrophages; SPP1; Silicosis.
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