Mechanically induced dysregulation of calcium homeostasis: a molecular linchpin in asthmatic pathogenesis.

Asthma is a heterogeneous chronic airway disease characterized by inflammation, hyperresponsiveness, mucus hypersecretion, and remodeling. Emerging evidence highlights calcium homeostasis imbalance as a central molecular hub integrating mechanical stress with immune-inflammatory responses. This review synthesizes recent mechanistic insights into how dysregulated calcium signaling-via transient receptor potential (TRP) channels (e.g., TRPV1, TRPA1), store-operated calcium entry (SOCE), L-type calcium channels (LTCCs), and mechanosensitive Piezo1-drives key asthma phenotypes. Calcium fluctuations triggered by mechanical stimulation disrupt the epithelial barrier. This process is achieved through activating calcium protease, which degrades E-cadherin and occludin, a tight junction protein. Simultaneously, it enhances the release of Th2-type cytokines (e.g., IL-4 and IL-13) and sustains the pathological state of mucosal cell proliferation via the TMEM16A channel. In airway smooth muscle, calcium dyshomeostasis enhances contractility via the myosin light-chain kinase (MLCK)/RhoA-ROCK axis and SOCE hyperactivation, while Piezo1-mediated mechano transduction exacerbates extracellular matrix (ECM) deposition and remodeling. We propose a bidirectional "calcium-barrier-inflammation vicious cycle" where mechanical stress and cytokines synergize to sustain pathology. Interventions targeting calcium-regulated nodes (such as STIM1-Orai1 and Piezo1) may provide a new direction for asthma treatment beyond traditional anti-inflammatory strategies.