The PIEZO1/CISD1/IP3R Mechanotransduction Axis Drives Macrophage Mitochondrial Dysfunction and Inflammatory Activation in Pulmonary Fibrosis

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and elevated tissue stiffness. While aberrant mechanotransduction is increasingly recognized as a key driver of fibrotic progression, the mechanisms by which mechanical cues orchestrate macrophage dysfunction remain poorly elucidated. Here, we identify the mechanosensitive ion channel PIEZO1 as a key mediator coupling matrix stiffening to macrophage inflammatory activation in pulmonary fibrosis. We demonstrate that PIEZO1 is substantially upregulated in fibrotic lungs, and that its activation drives intracellular calcium overload via the CISD1/IP3R signaling axis. This process elicits aberrant opening of the mitochondrial permeability transition pore (MPTP), causing mitochondrial dysfunction and augmented pro‐inflammatory macrophage polarization. Conversely, PIEZO1 inhibition suppresses the CISD1/IP3R signaling cascade, alleviates calcium dysregulation, prevents mitochondrial damage, and attenuates inflammatory activation. In vitro CISD1 inhibition ameliorates PIEZO1‐driven mitochondrial abnormalities and pro‐inflammatory signaling in macrophages. Furthermore, genetic knockdown of CISD1 mitigates mitochondrial abnormalities and attenuates bleomycin (BLM)‐induced lung fibrosis in mice. Collectively, these findings identify a previously unrecognized PIEZO1/CISD1/IP3R mechanotransduction axis coupling tissue stiffening to macrophage‐mediated inflammation and fibrosis. This study offers mechanistic insights into fibrosis‐associated immune dysregulation, highlighting PIEZO1 and CISD1 as promising therapeutic targets for pulmonary fibrosis.