Background <p>Silicosis is an incurable occupational lung disease characterized by progressive fibrosis and respiratory failure, imposing a significant global health burden. Surfactant protein A (SP-A) plays a critical role in maintaining pulmonary homeostasis, yet its mechanistic role in silicosis remains unclear.</p> Methods <p>SP-A expression was assessed in lung tissues from patients with silicosis and in silica-exposed mice. <i>Sftpa1</i> gene knockout (<i>Sftpa1</i>^<i>-/-</i>) mice were generated to evaluate the functional role of SP-A <i>in vivo</i>, including lung pathology, collagen deposition, and pulmonary function. RNA sequencing was performed to uncover underlying molecular mechanisms. A549 cells with SP-A silenced by siRNA were employed for <i>in vitro</i> experiments.</p> Results <p>SP-A levels were notably reduced in the lung tissue of silicosis patients and in experimental silicosis mice, correlating inversely with disease severity. <i>Sftpa1</i>^{<i>⁻/⁻</i>} mice showed markedly exacerbated silica-induced pulmonary fibrosis, extracellular matrix deposition, and functional decline. RNA-seq analysis highlighted activation of intrinsic apoptosis pathways related to pulmonary fibrosis. Mechanistically, SP-A deficiency disrupted the balance of Bcl-2 and Bax, activated Caspase-3, and promoted epithelial apoptosis. Inhibition of the intrinsic apoptosis pathway mitigated the pro-apoptotic effects of SP-A silencing.</p> Conclusions <p>These findings demonstrate that SP-A deficiency exacerbates silica-induced pulmonary fibrosis by promoting epithelial apoptosis involving the Bcl-2/Bax/Caspase pathway, highlighting the role of SP-A in fibrogenesis progression and providing a basis for its potential therapeutic target for silicosis.</p>