Lipid metabolism as a cell-state determinant in pulmonary fibrosis: from epithelial failure to ferroptosis-driven amplification.

Despite 2 decades 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.