Tirzepatide Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Association with the SIRT1/H4K12la/c-Jun Axis

Metabolic reprogramming and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) are critical pathological features of pulmonary arterial hypertension (PAH). Here, we demonstrated that Tirzepatide (TZP) can significantly ameliorate echocardiographic indicators of pulmonary vascular load and attenuate distal pulmonary vascular remodeling by suppressing PASMC phenotypic switching. Metabolomics and cellular metabolic flux analyses revealed that TZP corrected the Warburg effect, thereby attenuating intracellular lactate accumulation, which we identified as a driver that promotes the synthetic phenotype in PASMCs and exacerbates PAH. Mechanistically, the protective effects of TZP were strongly associated with the activation of the AMPK/SIRT1 signaling pathway, which mediated a significant reduction in histone H4 lysine 12 lactylation (H4K12la). This epigenetic reduction suppressed the transcription of the proto-oncogeneJunand its downstream pathways, which promote PASMC phenotypic switching and PAH deterioration. Thus, we propose a working model wherein TZP attenuates PAH progression by modulating pathological metabolism and reducing c-Jun transcription via the AMPK/SIRT1/H4K12la axis. These findings provide preliminary translational implications for targeting metabolic-epigenetic crosstalk and offer a preclinical rationale for exploring TZP as a protective pharmacological strategy in PAH.