Deletion of STIM1 in Treg cells protects against lung fibrosis and associated cardiovascular complications in a pre-clinical mouse model

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by excessive tissue remodeling and impaired gas exchange. Evidence highlights the critical interplay between immune regulation, calcium signaling, and redox biology implications in the pathogenesis of fibrotic lung disease. Regulatory T-cells (Tregs), known to modulate cardiovascular and immune function, are diminished in IPF, contributing to inflammation and tissue damage. Here, we demonstrate that the stromal interaction molecule 1 (STIM1), a key regulator of intracellular calcium homeostasis, is significantly upregulated in Treg cells isolated from IPF patients and mice subjected to bleomycin-induced lung injury. This upregulation is associated with increased Treg cell apoptosis, reduced Foxp3 expression, and exacerbation of pulmonary fibrosis and cardiac remodeling. Using Treg-specific STIM1 knockout mice (Treg^STIM1-/-), we show that genetic deletion of STIM1 preserves Treg cell survival and function, attenuates pulmonary fibrosis, and significantly reduces cardiac fibrosis and endothelial dysfunction. Importantly, Treg^STIM1-/- mice displayed preserved pulmonary endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) signaling, indicating protection of endothelial redox balance. The maintenance of NO bioavailability correlated with reduced parenchymal resistance, improved lung compliance, and enhanced survival during chronic fibrotic stress. Our findings uncover a novel STIM1-dependent mechanism regulating Treg cell viability and nitric oxide (NO) signaling during pulmonary fibrosis. These results reveal a previously unrecognized link between Treg survival and endothelial NO-dependent redox homeostasis in fibrotic lung disease. By preserving endothelial function and redox balance, deletion of STIM1 in Treg cells protects against fibrosis-associated pulmonary and cardiovascular complications, identifying STIM1 as a potential therapeutic target for restoring immune-redox balance in IPF.