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This study demonstrates that fecal microbiota transplantation (FMT) confers protection against RILI through modulation of the gut-lung axis. In a total lung irradiation (TLI) mouse model, FMT significantly alleviated pulmonary histopathological injury, inflammatory responses, oxidative stress, and collagen deposition during fibrogenesis. Concurrently, FMT improved intestinal motility, enhanced mucosal barrier integrity, and restored TLI-induced dysbiosis in gut microbiota diversity and community structure. Metabolomic analysis revealed that TLI significantly disrupted the metabolism of unsaturated fatty acids and arachidonic acid (AA), whereas FMT partially restored these metabolic networks. Transcriptomic and ultrastructural analyses indicated that RILI suppressed endoplasmic reticulum (ER) protein processing and induced ER swelling, while FMT promoted protective ER-phagy and facilitated restoration of ER morphology. Integrated multi-omics analysis further identified the AA metabolism as a key component of FMT-mediated protection, with its alterations closely associated with pulmonary tissue repair. Further\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments demonstrated that AA binds to and activates the nuclear receptor PPAR\u03b3, leading to transcriptional upregulation of FAM134B, promoting protective ER-phagy and ameliorating RILI. In summary, this study highlights the bidirectional gut-lung axis as a therapeutic target in RILI progression and intervention, and reveals that FMT confers protection through metabolic remodeling and activation of the PPAR\u03b3-FAM134B-mediated ER-phagy pathway, providing a mechanistic basis for potential clinical translation.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013786","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T18:37:41Z","timestamp":1769020661000},"page":"e1013786","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fecal microbiota transplantation ameliorates radiation-induced lung injury by reshaping gut metabolic homeostasis to activate FAM134B-mediated 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