{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:32:57Z","timestamp":1787045577735,"version":"build-2736575974"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"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. Med."],"abstract":"<jats:p>The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations\u2014including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and \u03b3\u03b4 T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53\/p21 and p16\/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)\u2013stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a \u201cspatial niche remodeling\u201d framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease\u2014from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.<\/jats:p>","DOI":"10.3389\/fmed.2026.1899423","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:10:06Z","timestamp":1787044206000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases"],"prefix":"10.3389","volume":"13","author":[{"given":"Fukang","family":"Mao","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Kunming Medical University","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keji","family":"Shan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Kunming Medical University","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1146\/annurev-immunol-051116-052415","article-title":"Immune responses in the liver","volume":"36","author":"Kubes","year":"2018","journal-title":"Annu Rev Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.3389\/fimmu.2019.02670","article-title":"Contribution of macrophage efferocytosis to liver homeostasis and disease","volume":"10","author":"Horst","year":"2019","journal-title":"Front Immunol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"10321","DOI":"10.1038\/ncomms10321","article-title":"Bone 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