{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:03:32Z","timestamp":1789981412818,"version":"4.0.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Despite 2\u00a0decades of mechanistic progress, pulmonary fibrosis still progresses in many patients, and established scar rarely resolves. Lipid metabolism has emerged as a unifying lens on this disease, but a useful synthesis requires recognizing that the relevant abnormalities are compartment-specific, stage-dependent, and unevenly supported by human evidence. Here we argue that lipid metabolism in pulmonary fibrosis is best understood as a determinant of cell-state stability, and that its failure plays out differently across three compartments. In alveolar epithelial cells, reduced lipogenesis, impaired fatty-acid oxidation, surfactant imbalance, and lipotoxic stress destabilize the regenerative AT2 state. This compartment exhibits the most consistent correlative human tissue associations reported to date. In fibroblasts, a shift away from fatty-acid oxidation toward anabolic and lipogenic programs likely stabilizes cells into a persistent myofibroblast identity at the expense of more reparative lipofibroblast-like states. In macrophages, altered lipid uptake, oxidized-lipid responses, and disturbed cholesterol handling support a profibrotic niche, with ontogeny and metabolic profile increasingly displacing classical M1\/M2 categories. These compartment-specific programs converge on a shared downstream amplifier, namely phospholipid peroxidation and ferroptosis, where the strongest evidence again concerns injured epithelium. Therapeutic strategies group naturally into three tiers: clinical anchors with indirect metabolic relevance, including pirfenidone, nintedanib, and PDE4B inhibition; repurposed agents with metabolic rationale, including metformin, ezetimibe, and PPAR and LXR modulators; and mechanism-driven, largely preclinical strategies targeting mitochondrial-redox balance and ferroptosis. Reframing lipid metabolism as a cell-state determinant clarifies which abnormalities are actionable, in which compartments they matter, and when intervention is most likely to alter disease course.<\/jats:p>","DOI":"10.3389\/fphar.2026.1917792","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:24:48Z","timestamp":1789979088000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipid metabolism as a cell-state determinant in pulmonary fibrosis: from epithelial failure to ferroptosis-driven amplification"],"prefix":"10.3389","volume":"17","author":[{"given":"Er","family":"Lin","sequence":"first","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhehua","family":"Shao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Yi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Geriatric Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghua","family":"Ying","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eaba1983","DOI":"10.1126\/sciadv.aba1983","article-title":"Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis","volume":"6","author":"Adams","year":"2020","journal-title":"Sci. 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