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While metabolic reprogramming is pivotal in macrophage activation, the role of amino acid metabolism\u2014particularly proline\u2014in regulating radiation-induced inflammation remains unexplored. In this study, bone marrow-derived macrophages (BMDMs) and RAW264.7 cells exposed to 4\u00a0Gy radiation exhibited robust M1 polarization (increasing from 13.5% in controls to 23.7% in F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD86\n                    <jats:sup>+<\/jats:sup>\n                    cells), elevated pro-inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, IL-6; 3- to 6-fold increase), and mitochondrial dysfunction ( 30% decrease in ATP levels, 60% reduction in oxygen consumption rate [OCR], and 2-fold increase in mitochondrial ROS). Proline supplementation reversed these effects, suppressing M1 polarization by 50%, restoring ATP levels by 1.6-fold, and normalizing oxidative phosphorylation. Mechanistically, radiation upregulated ATPIF1 (1.8-fold increase) and phosphorylated mTOR (p-mTOR; 3.2-fold increase), while proline abolished these changes (ATPIF1 decreased by 30%, p-mTOR reduced by 50%). RNA-seq and metabolomics linked proline to ATP metabolism and amino acid homeostasis. ATPIF1 knockdown abolished radiation-induced pro-inflammatory effects and eliminated proline\u2019s protective efficacy, confirming the ATPIF1-mTOR axis as the central regulatory mechanism. In a rat radiation colitis model, proline mitigated colon shortening, reduced histopathological damage, and decreased M1 macrophage infiltration. Collectively, our findings establish the ATPIF1-mTOR axis as a critical mediator of radiation-induced M1 macrophage polarization, which is effectively countered by proline supplementation.\n                  <\/jats:p>","DOI":"10.1007\/s10753-025-02404-3","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T19:15:48Z","timestamp":1772046948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Proline-Mediated Inhibition of ATPIF1-mTOR Signaling Alleviates Radiation-Induced Macrophage Polarization and Colon Inflammation"],"prefix":"10.1007","volume":"49","author":[{"given":"Lei","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhou","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renhuang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiguo","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"issue":"5","key":"2404_CR1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1667\/RR15398.1","volume":"192","author":"N Pham","year":"2019","unstructured":"Pham, N., M. 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