Idiopathic pulmonary fibrosis (IPF) is characterized by excessive fibroblast recruitment and persistent extracellular matrix deposition at sites of tissue injury, leading to severe morbidity and mortality. However, the precise mechanisms by which fibroblasts contribute to IPF pathogenesis remain poorly understood. The study reveals that Sema3E and its receptor Plexin D1 are significantly overexpressed in the lungs of IPF patients and bleomycin (BLM)-induced lung fibrotic mice. Elevated plasma levels of Sema3E in IPF patients are negatively correlated with lung function. Importantly, Sema3E in IPF lungs predominantly exists as the P61-Sema3E. The knockdown of Sema3E or Plexin D1 effectively inhibits fibroblast activation, proliferation, and migration. Mechanistically, Furin-mediated cleavage of P87-Sema3E into P61-Sema3E drives these pro-fibrotic activities, with P61-Sema3E-PlexinD1 axis promoting fibroblast activation, proliferation, and migration by affecting the phosphorylation of ErbB2, which subsequently activates the ErbB2 pathways. Additionally, Furin inhibition reduces fibroblast activity by decreasing P61-Sema3E production. In vivo, both whole-lung Sema3E knockdown and fibroblast-specific Sema3E knockout confer protection against BLM-induced lung fibrosis. These findings underscore the crucial role of the P61-Sema3E-Plexin D1 axis in IPF pathogenesis and suggest that targeting this pathway may hold promise for the development of novel therapeutic strategies for IPF treatment.