Gene · 2026
Integrative single‑cell and bulk transcriptomic profiling reveals MMP1 as a core effector and CTSB as a putative collaborator in ATBC‑aggravated pulmonary fibrosis.
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Fu Dajia, Ding Xiuxiu, Cai Xinyi, Ouyang Yanhong, Wei Chaochao
Аннотация
BACKGROUND: Acetyl tributyl citrate (ATBC) is a widely used environmentally friendly plasticizer, and exposure via the respiratory tract is common in the general population. However, its pulmonary toxicity and underlying molecular mechanisms remain poorly understood.
METHODS: An integrative strategy combining compound target prediction, IPF transcriptome screening, Bootstrap LASSO stability selection, and protein‑protein interaction network topological analysis was used to identify core targets. Single-cell transcriptomics was applied to dissect the cellular localization and functional roles of these targets. A bleomycin‑induced mouse pulmonary fibrosis model was employed to assess the effects of intratracheal instillation exposure to ATBC.
RESULTS: Two core targets, MMP1(matrix metalloproteinase-1) and CTSB(cathepsin B), were identified from 17 candidate genes. Single-cell analysis revealed that MMP1 exhibits an "off-on" regulatory pattern in airway epithelial club cells-it is not expressed under steady‑state conditions but is specifically induced upon activation. In contrast, CTSB is highly expressed in macrophages and enhances pro‑fibrotic communication. The two targets exert complementary functions: MMP1⁺club cells enter a translationally hyperactive state involved in basement membrane remodeling, while CTSB⁺ macrophages amplify pro‑fibrotic signaling. Animal experiments showed that ATBC dose‑dependently exacerbates pulmonary fibrosis and upregulates MMP1 protein expression.
CONCLUSIONS: Intratracheal instillation exposure to ATBC may aggravate fibrosis progression on the basis of pre‑existing lung injury, with MMP1 serving as a core effector molecule. These findings offer preliminary experimental support for the safety assessment of plasticizers following respiratory tract exposure.
METHODS: An integrative strategy combining compound target prediction, IPF transcriptome screening, Bootstrap LASSO stability selection, and protein‑protein interaction network topological analysis was used to identify core targets. Single-cell transcriptomics was applied to dissect the cellular localization and functional roles of these targets. A bleomycin‑induced mouse pulmonary fibrosis model was employed to assess the effects of intratracheal instillation exposure to ATBC.
RESULTS: Two core targets, MMP1(matrix metalloproteinase-1) and CTSB(cathepsin B), were identified from 17 candidate genes. Single-cell analysis revealed that MMP1 exhibits an "off-on" regulatory pattern in airway epithelial club cells-it is not expressed under steady‑state conditions but is specifically induced upon activation. In contrast, CTSB is highly expressed in macrophages and enhances pro‑fibrotic communication. The two targets exert complementary functions: MMP1⁺club cells enter a translationally hyperactive state involved in basement membrane remodeling, while CTSB⁺ macrophages amplify pro‑fibrotic signaling. Animal experiments showed that ATBC dose‑dependently exacerbates pulmonary fibrosis and upregulates MMP1 protein expression.
CONCLUSIONS: Intratracheal instillation exposure to ATBC may aggravate fibrosis progression on the basis of pre‑existing lung injury, with MMP1 serving as a core effector molecule. These findings offer preliminary experimental support for the safety assessment of plasticizers following respiratory tract exposure.