2. Academic Validation
  3. Phosphatase PHLPP1 is an alveolar-macrophage-intrinsic transcriptional checkpoint controlling pulmonary fibrosis

Phosphatase PHLPP1 is an alveolar-macrophage-intrinsic transcriptional checkpoint controlling pulmonary fibrosis

  • Cell Rep. 2025 Mar 25;44(3):115399. doi: 10.1016/j.celrep.2025.115399.
Yuyu Jiang 1,  Yunkai Zhang 2,  Xiaohui Wang 3,  Yan Xiang 4,  Zeting Wang 4,  Bo Wang 5,  Yingying Ding 4,  Ying Gao 6,  Bing Rui 4,  Jie Bai 4,  Yue Ding 4,  Chang Chen 7,  Zhenzhen Zhan 8,  Xingguang Liu 9
Affiliations

Affiliations

  • 1 National Key Laboratory of Immunity & Inflammation, Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 2 Naval Medical Center, Naval Medical University, Shanghai 200433, China.
  • 3 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 4 National Key Laboratory of Immunity & Inflammation, Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China.
  • 5 Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 6 Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
  • 7 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 8 Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: zhanzz@tongji.edu.cn.
  • 9 National Key Laboratory of Immunity & Inflammation, Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China. Electronic address: liuxg@immunol.org.
PMID: 40085643 DOI: 10.1016/j.celrep.2025.115399
Abstract

Alveolar macrophages (AMs) are crucial for lung homeostasis, and their dysfunction causes uncontrolled fibrotic responses and pulmonary disorders. Protein phosphatases control multiple cellular events. However, whether nuclear phosphatases cooperate with histone modifiers to affect pulmonary fibrosis progress remains obscure. Here, we identified pleckstrin homology domain and leucine-rich repeat protein Phosphatase 1 (PHLPP1) as a key protective factor for pulmonary fibrosis. Transcriptomics and epigenomics data confirmed that PHLPP1 selectively targeted Kruppel-like factor 4 (KLF4) for transcriptional inhibition in AMs. Nuclear PHLPP1 directly bound and dephosphorylated histone deacetylase 8 (HDAC8) at serine 39, thereby enhancing its deacetylase Enzyme activity and subsequently suppressing KLF4 expression via the decreased histone acetylation and chromatin accessibility. Thus, loss of PHLPP1 amplified KLF4-centric profibrotic transcriptional program in AMs, while intratracheal administration of Klf4-short hairpin RNA (shRNA) adeno-associated virus ameliorated lung fibrosis in PHLPP1-deficient mice. Our study implies that targeting decreased PHLPP1 in AMs might be a promising therapeutic strategy for pulmonary fibrosis.

Keywords

CP: Immunology; CP: Molecular biology; KLF4; PHLPP1; alveolar macrophage; histone acetylation; protein phosphatase; pulmonary fibrosis.

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