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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\u2010cell RNA sequencing and spatial transcriptomics reveal alveolar type 2 epithelial cells as the primary site of Hcy metabolism, with downregulation of Hcy\u2010catabolizing enzyme methionine synthase reductase (\n                    <jats:italic>MTRR<\/jats:italic>\n                    ) during fibrotic progression. Genetic perturbation studies in murine models demonstrate that\n                    <jats:italic>MTRR<\/jats:italic>\n                    knockdown exacerbates bleomycin\u2010induced mortality and fibrosis, whereas\n                    <jats:italic>MTRR<\/jats:italic>\n                    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\u2013ubiquitination 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\u2013STX17\u2013proteostasis axis wherein excess homocysteinylation creates a self\u2010reinforcing loop of autophagy dysfunction and fibrogenesis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507803","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:30:59Z","timestamp":1758717059000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Homocysteine Exacerbates Pulmonary Fibrosis via Orchestrating Syntaxin 17 Homocysteinylation of Alveolar Type II Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiefeng","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai 200072 China"},{"name":"School of Medicine Tongji University Shanghai 200331 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