2. Academic Validation
  3. Elevated lactate production exacerbates PM2.5-induced pulmonary fibrosis by stabilizing TGF-β1

Elevated lactate production exacerbates PM2.5-induced pulmonary fibrosis by stabilizing TGF-β1

  • J Adv Res. 2025 Aug 5:S2090-1232(25)00587-9. doi: 10.1016/j.jare.2025.07.057.
Zhihao Liu 1,  Wei Liu 2,  Huaiqing Wei 3,  Yiping Ping 1,  Zhenjie Yu 4,  Zheng Dong 1,  Jiayu Ren 1,  Shuping Zhang 5,  Sijin Liu 6
Affiliations

Affiliations

  • 1 School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 2 School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. Electronic address: weijielietu@163.com.
  • 3 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 4 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
  • 5 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 6 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
PMID: 40759348 DOI: 10.1016/j.jare.2025.07.057
Abstract

Introduction: Lactate, a glycolysis byproduct, has been implicated in the fibrotic process, while transforming growth factor-beta 1 (TGF-β1) plays a central role in promoting fibrosis. Air pollution, particularly fine particulate matter (PM2.5), represents a significant environmental risk factor for the development of pulmonary fibrosis. However, the role of lactate and the underlying mechanisms by which it acts in PM2.5-induced pulmonary fibrosis remain poorly understood.

Objectives: This study aimed to identify the cell types contributing to lactate accumulation in lung tissue during PM2.5-induced pulmonary fibrosis and elucidate the mechanism by which lactate regulates TGF-β1.

Methods: Seven types of lung cells from PM2.5-exposed mice were isolated using fluorescence-activated cell sorting to determine their lactate production. Immunoprecipitation and immunoblotting were performed to assess the impact of lactate on TGF-β1 stability. The effect of histone lactylation on Stub1 gene expression was investigated by chromatin immunoprecipitation assays.

Results: Macrophages exhibited elevated lactate production during PM2.5-induced pulmonary fibrosis. Elevated intracellular lactate levels in macrophages suppressed the expression of carboxyl terminus of Hsc70-interacting protein (CHIP, encoded by Stub1) via the enrichment of lactylated H3K18 at the Stub1 promoter locus. Consequently, reduced CHIP expression impeded TGF-β1 degradation, promoted enhanced TGF-β1 secretion by macrophages, and exacerbated pulmonary fibrosis symptoms. Moreover, the inhibition of lactate production significantly alleviated the pulmonary fibrosis phenotype in PM2.5-exposed mice.

Conclusion: Elevated lactate production in macrophages induced by PM2.5 inhibits the ubiquitination and degradation of TGF-β1 through the suppression of CHIP expression, thereby enhancing TGF-β1 secretion and exacerbating pulmonary fibrosis.

Keywords

Lactate; Lactylation; PM2.5; Pulmonary fibrosis; TGF-β1.

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