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

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.