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Homocysteine Exacerbates Pulmonary Fibrosis via Orchestrating Syntaxin 17 Homocysteinylation of Alveolar Type II Cells The study identifies elevated homocysteine (Hcy) levels in idiopathic pulmonary fibrosis patients' samples, with alveolar type 2 cells as the primary site of Hcy metabolism. Methionine synthase reductase downregulation in these cells exacerbates fibrosis, while folate administration reduces Hcy levels and alleviates fibrosis. Mechanistically, Hcy drives Syntaxin 17 (STX17) degradation via homocysteinylation–ubiquitination, disrupting autophagy. Folate restores STX17 levels and mitigates fibrosis. Abstract Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease, marked by progressive extracellular matrix deposition, for which there are no effective treatments to halt disease progression. Although hyperhomocysteinemia is implicated in multiple pathological processes, its role in IPF remains largely unexplored. Through multiomics profiling of IPF patients, significantly elevated homocysteine (Hcy) concentrations in plasma and bronchoalveolar lavage fluid are identified compared to healthy controls. Single-cell RNA sequencing and spatial transcriptomics reveal alveolar type 2 epithelial cells as the primary site of Hcy metabolism, with downregulation of Hcy-catabolizing enzyme methionine synthase reductase ( MTRR ) during fibrotic progression. Genetic perturbation studies in murine models demonstrate that MTRR knockdown exacerbates bleomycin-induced mortality and fibrosis, whereas MTRR overexpression exerts protective effects. Furthermore, Hcy supplementation initiates and accelerates pulmonary fibrosis development, while folate administration reduces pulmonary Hcy levels and alleviates fibrosis. Mechanistically, it is revealed that pathogenic hyperhomocysteinemia induces homocysteinylation–ubiquitination cascades that modify Syntaxin 17 (STX17) posttranslationally, leading to its proteasomal degradation and consequent impairment of autophagic flux. Notably, pharmacological folate administration reverses STX17 depletion, restoring autophagic flux and mitigating pulmonary fibrosis in mouse models. These findings collectively establish a Hcy–STX17–proteostasis axis wherein excess homocysteinylation creates a self-reinforcing loop of autophagy dysfunction and fibrogenesis. https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202507803?af=R