Macrophage‐to‐Myofibroblast Transdifferentiation Contributes to Pulmonary Fibrosis via the MERTK‐SPP1‐SRC‐TKS5 Signaling Axis

ABSTRACT In recent years, macrophage‐to‐myofibroblast transdifferentiation (MMT) has been found in fibrosis‐related diseases. We confirmed the presence of MMT in human idiopathic pulmonary fibrosis (IPF) lungs and bleomycin‐induced murine model using immunological and molecular methods. Mechanistically, ligand (GAS6)‐mediated activation of MERTK on macrophages initiates a sequential signaling cascade involving SPP1, SRC, and TKS5, which collectively drives the transdifferentiation program. Conversely, knockout of MERTK specifically in macrophages or adeno‐associated virus (AAV)‐mediated knockdown of TKS5 effectively disrupted this MERTK‐SPP1‐SRC‐TKS5 axis, potently suppressing MMT in vitro and in vivo. These interventions significantly attenuated the progression of pulmonary fibrosis, as evidenced by comprehensive assessments including microCT, pulmonary function test, and histopathological analysis. Our findings establish MMT as a key pathogenic mechanism and identify the MERTK‐initiated signaling axis as a novel therapeutic target.