LAUSR

Significance Stromal-interacting molecule 1 (STIM1) proteins are essential for the function of store-operated Ca2+ entry (SOCE). Using transcriptomics, metabolomics, imaging, and inducible smooth muscle–specific STIM1 knockout mice expressing genetically encoded Ca2+ sensors, we reveal a crucial function of STIM1 in airway remodeling and airway hyperresponsiveness in asthma. STIM1-mediated Ca2+ oscillations in airway smooth muscle (ASM) cells are critical for ASM remodeling through metabolic and transcriptional reprogramming and cytokine secretion, including IL-6. These effects are driven by Ca2+-dependent activation of the transcription factor isoform NFAT4 specifically in ASM. Our data provide evidence that ASM STIM1 and SOCE are central triggers of asthma manifestations and advocate for the future use of STIM1 as a molecular target in asthma therapy. Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.