{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:12:16Z","timestamp":1792005136985,"version":"4.4.0"},"reference-count":79,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"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":"publisher","award":["82574202"],"award-info":[{"award-number":["82574202"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173619"],"award-info":[{"award-number":["82173619"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82574202"],"award-info":[{"award-number":["82574202"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82173619"],"award-info":[{"award-number":["82173619"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hainan Province Science and Technology Special Fund","award":["ZDYF2025SHFZ046"],"award-info":[{"award-number":["ZDYF2025SHFZ046"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Tumor-associated macrophages (TAMs) are key components of the hepatocellular carcinoma (HCC) microenvironment, but their spatial heterogeneity remains incompletely characterized. We aimed to assess the biological and prognostic relevance of a BAG3-associated TAM program in HCC. Methods: Public single-cell RNA sequencing (scRNA-seq) datasets were analyzed to characterize TAM heterogeneity, and an integrated validation scRNA-seq dataset was used to assess reproducibility. Spatial transcriptomics was used to provide spatial context in a small treatment-exposed cohort. Pseudotime, regulatory network, and cell\u2013cell communication analyses were performed to characterize state transitions and microenvironmental interactions. Survival modeling evaluated the prognostic relevance of the BAG3-associated program. Results: Five TAM subsets were identified, including MARCO+, MT+ RTM\u2212, MMP9+, UBE2C+, and BAG3+ TAMs. Among them, BAG3+ TAMs, a less well-characterized subset, exhibited coordinated stress-adaptive, proteostasis-related, and matrix-remodeling programs that were reproduced in the validation dataset. Pseudotime analysis suggested a continuum of TAM states, with BAG3+ TAM stress-remodeling features enriched toward late pseudotime. Communication analysis centered on BAG3+ TAMs suggested crosstalk between inflammatory stress cues and angiogenic, stromal-remodeling, and immunomodulatory programs; this pattern was primarily supported by HBV-derived samples and recurrently involved the MIF\u2013CD74 axis. Spatial mapping further supported BAG3+ TAM-enriched niches with elevated AP-1, EGR1, and NFKB1 activity. A BAG3-associated risk score derived from a 10-gene signature remained an independent prognostic factor for overall survival after clinical adjustment. Conclusions: These findings characterize a BAG3-associated TAM program with spatial, immunoregulatory, and prognostic relevance in HCC, and support its further evaluation in biomarker and mechanistic studies.<\/jats:p>","DOI":"10.3390\/genes17050562","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:07:26Z","timestamp":1779206846000},"page":"562","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Single-Cell and Spatial Transcriptomics Analyses Delineate a BAG3-Associated Macrophage Program with Microenvironmental and Prognostic Relevance in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0916-8023","authenticated-orcid":false,"given":"Ruixiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9215-6874","authenticated-orcid":false,"given":"Yifang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1199-9778","authenticated-orcid":false,"given":"Junda","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9106-8623","authenticated-orcid":false,"given":"Yuansheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7080-6858","authenticated-orcid":false,"given":"Zuming","family":"You","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6311-9307","authenticated-orcid":false,"given":"Chenxi","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Clinical Research Centre, School of Medicine, The Second Affiliated Hospital of South China University of Technology (Guangzhou First People\u2019s Hospital), Guangzhou 510180, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0866-4402","authenticated-orcid":false,"given":"Jiyuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health (State Key Laboratory of Multi-Organ Injury Prevention and Treatment, and Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"Ca. 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