{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:34:53Z","timestamp":1783434893652,"version":"3.54.6"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82574020"],"award-info":[{"award-number":["82574020"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82473565"],"award-info":[{"award-number":["82473565"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["U24A20765"],"award-info":[{"award-number":["U24A20765"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation","award":["2023HYX005"],"award-info":[{"award-number":["2023HYX005"]}]},{"name":"Suzhou Fundamental Research Project","award":["SJC2023001"],"award-info":[{"award-number":["SJC2023001"]}]},{"name":"Open Project of Key Laboratory of Nuclear and Radiation Damage Mechanisms and Treatment Technologies","award":["2024ZX01"],"award-info":[{"award-number":["2024ZX01"]}]},{"DOI":"10.13039\/501100012166","name":"National key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2503700"],"award-info":[{"award-number":["2022YFC2503700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2503703"],"award-info":[{"award-number":["2022YFC2503703"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["U24A20765"],"award-info":[{"award-number":["U24A20765"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Internal Collaboration Project of Jiangsu Radiation Medicine Collaborative Innovation Center","award":["FY202401"],"award-info":[{"award-number":["FY202401"]}]},{"name":"A Project of the State Key Laboratory of Radiation Medicine and Protection","award":["GZK12024032"],"award-info":[{"award-number":["GZK12024032"]}]},{"name":"A Project of the State Key Laboratory of Radiation Medicine and Protection","award":["GZK12024035"],"award-info":[{"award-number":["GZK12024035"]}]},{"name":"Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions"},{"name":"Key Scientific Research Projects of Jiangsu Provincial Health Commission","award":["ZD2021053"],"award-info":[{"award-number":["ZD2021053"]}]},{"name":"Suzhou Fundamental Research Project","award":["SJC2023001"],"award-info":[{"award-number":["SJC2023001"]}]},{"DOI":"10.13039\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Kupffer cells (KCs) make up the predominant population of resident innate immune cells in the liver, serving as key immune sentinels that maintain local immune surveillance and immunoregulatory homeostasis. However, their functional involvement and phenotypic dynamics during radiation-induced liver damage (RILD) remain insufficiently explored. Therefore, we established a mouse model of RILD and, through systematic single-cell-level profiling of hepatic immune cell populations, found that KCs play a critical role in hepatic immune responses and undergo a pronounced radiation-induced shift toward a pro-inflammatory M1 phenotype. Further KC depletion\/reconstitution, molecular assays, and coculture experiments consistently demonstrated that M1-polarized KCs exacerbate liver damage, with secretory leukocyte protease inhibitor (SLPI) being identified as a key molecular mediator driving this polarization and its pathogenic effects. To further substantiate these findings, we designed a liposome-based delivery strategy to selectively inhibit SLPI in KCs, which effectively suppressed M1 polarization and alleviated radiation-induced liver damage, underscoring the therapeutic relevance and translational potential of this approach in RILD. Overall, these findings demonstrate that radiation drives KCs toward an SLPI-dependent pro-inflammatory M1 state, thereby exacerbating liver injury. Moreover, targeted liposomal suppression of SLPI effectively reverses this polarization and protects against RILD, highlighting SLPI-modulated KC reprogramming as a promising therapeutic approach.<\/jats:p>","DOI":"10.3390\/ijms27052517","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:16:03Z","timestamp":1773076563000},"page":"2517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SLPI-Loaded Liposomes Targeting Kupffer Cells Modulate Macrophage Polarization and Mitigate Radiation-Induced Liver Damage"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9819-3491","authenticated-orcid":false,"given":"Nan","family":"Yuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4047-2988","authenticated-orcid":false,"given":"Shihong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-029X","authenticated-orcid":false,"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5452-5553","authenticated-orcid":false,"given":"Yang","family":"Jiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Key Laboratory of Radiation Damage and Treatment of Jiangsu Provincial Universities and Colleges, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s10068-022-01118-8","article-title":"Amelioration of radiation-induced liver damage by p-coumaric acid in mice","volume":"31","author":"Li","year":"2022","journal-title":"Food Sci. 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