{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:05:09Z","timestamp":1789967109812,"version":"4.0.1"},"reference-count":54,"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Efferocytosis is a macrophage-dependent process responsible for clearing apoptotic cells. Reduced efferocytic capacity may be one of the factors contributing to liver cirrhosis (LC). This research aimed to identify and validate efferocytosis-related genes (EFRGs) associated with LC and investigate their potential roles in LC pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bulk RNA sequencing (bulk RNA-seq) analysis was performed to identify LC-assoated differentially expressed EFRGs and assess alterations in the immune microenvironment. Machine learning models combined with Shapley Additive Explanations (SHAP) analysis were used to screen hub genes. Single-cell RNA sequencing (scRNA-seq) analysis was performed to determine the cellular localization of galectin-3 (LGALS3) and explore the differences in efferocytic capacity among macrophage subpopulations and the potential involvement of LGALS3. NicheNet analysis and molecular structure modelling were used to screen candidate receptors, with further prioritization based on gene expression patterns. Immunohistochemistry (IHC), immunofluorescence (IF), and western blot (WB) were further used to validate hub gene expression and efferocytic activity and explore the downstream mechanism of the hub gene. To further evaluate the role of macrophage-derived LGALS3 in hepatic stellate cell (HSC) activation, LGALS3 was silenced by siRNA in polarised inflammatory macrophages before Transwell co-culture with JS1 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LGALS3 was identified as a hub EFRG positively associated with LC. LGALS3 expression tended to increase during liver fibrosis progression and was significantly higher in human and mouse cirrhotic tissues than in normal liver tissues. Moreover, LGALS3 expression was associated with immune infiltration characteristics in LC samples. scRNA-seq analysis revealed that LGALS3 was localized mainly to inflammatory macrophages and was significantly upregulated in this macrophage subset in LC tissues. LGALS3 marks a pro-inflammatory, low efferocytic capacity hepatic macrophage state. Based on gene expression pattern, together with molecular dynamics simulations, and experimental validation prioritised annexin A2 (ANXA2) as a candidate receptor potentially involved in LGALS3-mediated HSC activation. Consistently, silencing LGALS3 in inflammatory macrophages attenuated the upregulation of ANXA2 and \u03b1-SMA in co-cultured JS1 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>As a key EFRG in LC pathogenesis, LGALS3 marked a pro-inflammatory hepatic macrophage state with low efferocytic capacity and promoted HSC activation, potentially through ANXA2 as a candidate receptor for inflammatory macrophage-derived LGALS3.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1891906","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:28:34Z","timestamp":1789964914000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["LGALS3 marks a pro-inflammatory, efferocytosis-low hepatic macrophage state and promotes hepatic stellate cell activation through the candidate receptor ANXA2 in liver cirrhosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Fengchun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihan","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram Prasad","family":"Chaulagain","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuihua","family":"Li","sequence":"additional","affiliation":[{"name":"Digestive Endoscopic Center, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ni","sequence":"additional","affiliation":[{"name":"Digestive Endoscopic Center, The Second Affiliated Hospital, Harbin Medical University","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhu","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical 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