Tacrolimus ameliorates pulmonary hypertension associated with pulmonary fibrosis via modulation of vascular remodeling

Introduction Idiopathic pulmonary fibrosis (IPF) is frequently complicated by pulmonary hypertension (IPF-PH), a severe condition that worsens symptoms, reduces exercise capacity, and shortens survival. Current anti-fibrotic and PH-targeted therapies show limited efficacy in IPF-PH, and the therapeutic role of tacrolimus in this composite disease remains underexplored. Methods A bleomycin-induced IPF-PH rat model was established. Rats were randomized into control, bleomycin model, treprostinil (positive control), and tacrolimus (0.05 mg/kg/day, subcutaneous, 21 days) groups. Right ventricular systolic pressure (RVSP), echocardiography, right ventricular and lung histology, immunohistochemistry, qRT-PCR, and Western blot were assessed. In vitro, C166 endothelial cells and primary rat pulmonary arterial endothelial cells were stimulated with bleomycin with or without tacrolimus; MOVAS smooth muscle cells were stimulated with TGF-β1 with or without tacrolimus. Endpoints included cell viability, tube formation, ROS, SOD/GSH, apoptosis, proliferation/migration, and MAPK/PI3K/AKT signaling. Results Tacrolimus reduced RVSP, improved PAT/PET and right heart function, attenuated right ventricular hypertrophy and pulmonary fibrosis, and decreased vascular wall thickness and α-SMA expression. It also downregulated fibrosis markers Fn1 and Col1a1. In endothelial cells, tacrolimus restored P-VEGFR2/VEGFR2 and VE-cadherin expression, promoted tube formation, reduced apoptosis (Bax/Bcl-2, cleaved caspase-9/3), and alleviated oxidative stress (ROS, SOD/GSH, Keap1/HO-1). In smooth muscle cells, tacrolimus inhibited TGF-β1-induced proliferation and migration and reduced Ki67 expression. Mechanistically, tacrolimus suppressed MAPK (JNK, ERK, p38) and PI3K/AKT pathway activation in vivo and in vitro . Discussion Tacrolimus ameliorates bleomycin-induced IPF-PH through vascular remodeling-oriented, multi-target effects, including endothelial protection, suppression of oxidative stress and apoptosis, and inhibition of smooth muscle proliferation, partly via MAPK and PI3K/AKT signaling. These findings support tacrolimus as a potential therapeutic candidate for IPF-PH, especially in patients with prominent vascular remodeling, while highlighting the need for further dose-response, target-specific, immunomodulatory, and delivery optimization studies before clinical translation.