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September 10, 2025Open Access

The regulatory role of FABP4 in macrophage polarization and lipid accumulation in silicosis

Key Points

Inhibiting FABP4 showed reduced M1 polarization and lipid deposition in macrophages, indicating its role in silicosis.
FABP4 expression and inflammatory markers like IL-1β and TNF-α were elevated in silicosis patients, highlighting tissue responses.
Silica treatment enhanced FABP4 and lipid droplet accumulation in cell models, linking exposure to metabolic changes.
The PI3K/AKT/mTOR pathway was activated in macrophages via FABP4, suggesting a mechanism for increased inflammatory responses.

Abstract

Silicosis is a progressive pulmonary fibrosis, typically associated with occupational exposure to SiO2. Currently, there is no effective treatment for it. Macrophages are the first line of defense against inhaled dust in the lungs, and the inflammatory response and lipid metabolism disorder initiated by them are the key pathological mechanisms of silicosis. In this study, we first observed the lipid metabolism disorder and inflammatory response level in patients with silicosis, and then explored the mechanism of macrophage polarization and lipid metabolism disorder, especially the mechanism of the highly specific intracellular lipid transporter FABP4. The results showed that the expression of FABP4, inflammatory factors and lipid metabolism related indicators, such as IL-1β, IL-6, TNF-α, TC, TG, LDL-C and CD36 were increased in silicosis patients and alveolar macrophages, while the expression of LXR and ABCA1 was lower than that in the control group. In addition, SiO2 treatment also enhanced the expression of FABP4 in mice and RAW264.7 cells, increased lipid droplet deposition, and the cellular content of TC, FC and TG in RAW264.7 cells. Inhibiting FABP4 can suppress M1 polarization of RAW264.7 cells and reduce intracellular TC, FC and TG levels. Furthermore, FABP4 upregulation after SiO2 treatment seemed to activate the PI3K/AKT/mTOR signaling pathway in RAW264.7 cells, and the expression of p-PI3K, p-AKT, and p-mTOR increased. Inhibition of FABP4 can weaken the activation of the PI3K/AKT/mTOR pathway, M1 polarization and intracellular lipid deposition. Similarly, the PI3K inhibitor LY294002 can inhibit SiO2-induced macrophage polarization, reduce the intracellular contents of TC, FC and TG, and prevent lipid deposition. In conclusion, our results suggest that patients with silicosis and alveolar macrophages exhibit lipid metabolism disorder and inflammatory response. FABP4 plays a role in the progression of silicosis by regulating the activation of the PI3K/AKT/mTOR pathway, participating in SiO2-induced M1 polarization of macrophages and the accumulation of intracellular cholesterol components.

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