STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

Significance Stromal-interacting molecule 1 (STIM1) proteins are essential for the function of store-operated Ca 2+ entry (SOCE). Using transcriptomics, metabolomics, imaging, and inducible smooth muscle–specific STIM1 knockout mice expressing genetically encoded Ca 2+ sensors, we reveal a crucial function of STIM1 in airway remodeling and airway hyperresponsiveness in asthma. STIM1-mediated Ca 2+ 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 Ca 2+ -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.