Tet2 deficiency-induced expansion of monocyte-derived macrophages promotes liver fibrosis

  • J Exp Med. 2026 Feb 2;223(2):e20251114. doi: 10.1084/jem.20251114.
Jiuxing Feng  #  1 ,  Baitong Wu  #  2 ,  Yu Li  1 ,  Pengli Sun  1 ,  Qian Liu  1 ,  Qianxue Xiao  1 ,  Jia-Bin Cai  1 ,  Yimin Zheng  1 ,  Haonan Chen  1 ,  Yichi Xu  3 ,  Yixin Liu  1 ,  Guo-Ming Shi  1 ,  Li Tan  1  4 ,  Yujiang Geno Shi  1
Affiliations
  • 1. The Shanghai Key Laboratory of Medical Epigenetics, Liver Cancer Institute, Institutes of Biomedical Sciences and Zhongshan Hospital, Fudan University , Shanghai, P.R. China.
  • 2. East Hospital, Stem Cell Research Center, School of Medicine, Tongji University , Shanghai, P.R. China.
  • 3. Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
  • 4. Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Centre and Shanghai Key Laboratory of Medical Epigenetics, Fudan University , Shanghai, PR. China.
  • # Contributed equally.
PMID: 41474968 DOI: 10.1084/jem.20251114
Abstract

Clonal hematopoiesis driven by TET2 deficiency in myeloid cells (TetΔMye) is prevalent in elderly individuals; however, the role of Tet2ΔMye in liver fibrosis pathogenesis remains elusive. In this study, we demonstrated that Tet2-deficient monocyte-derived macrophages (MDMs) promoted cellular expansion and elevated C-C motif chemokine ligand 2/8 (Ccl2/8) secretion by stabilizing their mRNAs through 5hmC-mediated alterations in RNA-protein interactions. These chemokines engaged with the upregulated C-C motif Chemokine Receptor (CCR2/3) on Tet2-/- monocytes, forming a positive feedback loop that amplified pro-inflammatory MDMs (pMDMs) accumulation in liver. Tet2-/- pMDMs activated hepatic stellate cells through IL-6, driving extracellular matrix deposition and fibrotic progression. Pharmacological inhibition of Ccl2/Ccl8 with Bindarit attenuated MDMs accumulation and liver fibrosis, whereas combined therapy with Bindarit and IL-6 neutralization synergistically suppressed liver fibrosis in Tet2ΔMye mice and aged chimeric models recapitulating Tet2ΔMye-related myeloid hematopoiesis. These findings present the mechanism that Tet2ΔMye aggravates liver fibrosis and highlight MDMs depletion plus IL-6 neutralization as a promising therapy for liver fibrosis in patients with Tet2ΔMye-related myeloid hematopoiesis.

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