Therapeutic Targeting of the Macrophage YTHDC1/TIGAR/NF-κB Axis Mitigates Pulmonary Hypertension

Abstract

Abstract Rationale Immune dysregulation is a pivotal driver of pulmonary hypertension (PH) pathogenesis, yet therapeutic targeting of inflammation has yielded limited clinical success. Although cytosolic RNA-binding proteins are known to regulate immune responses in PH, the specific role of the nuclear m⁶A reader YTHDC1 remains undefined. Objectives To elucidate the function of macrophage YTHDC1 in orchestrating inflammatory vascular remodeling during PH. Methods Expression profiles of YTHDC1 and TP53-induced glycolysis and apoptosis regulator (TIGAR) were evaluated in human and rodent PH specimens. The mechanistic and therapeutic roles of this axis were assessed using myeloid-specific knockout mice and pharmacological inhibitors (YL-5092, 5Z-7-oxozeaenol) across hypoxia-, SU5416/hypoxia-, and monocrotaline-induced PH models. Measurements and Main Results In patients with idiopathic or connective tissue disease-associated PAH, YTHDC1 and TIGAR expression levels were elevated in pulmonary and circulating macrophages, correlating with disease severity. In murine models, myeloid-specific deletion of Ythdc1 or Tigar conferred profound protection against hypoxia- and SU5416/hypoxia-induced PH. Mechanistically, hypoxia upregulated Ythdc1, which directly bound and stabilized Tigar mRNA. The subsequent accumulation of Tigar protein operated non-enzymatically via a specific domain (residues 152-161) to interact with Tak1, thereby activating the NF-κB cascade, augmenting pro-inflammatory cytokine release, and driving pulmonary artery smooth muscle cell proliferation. Pharmacological inhibition of YTHDC1 (YL-5092) or disruption of the TIGAR-TAK1 interaction (5Z-7-oxozeaenol) effectively attenuated vascular inflammation and mitigated PH progression in diverse rodent models. Conclusions The macrophage YTHDC1/TIGAR/NF-κB signaling axis acts as a critical determinant of inflammation and vascular remodeling in PH, representing a potential biomarker and therapeutic target for this disease.