Liver Research最新文献

{"title":"Context-dependent duality of senescent cells in liver fibrosis","authors":"Yuqi Gu,&nbsp;Linjing Zhan,&nbsp;Yaping Di,&nbsp;Haipeng Wu,&nbsp;Tiejun Zhao,&nbsp;Fei Zhang,&nbsp;Qirou Wu","doi":"10.1016/j.livres.2026.09.001","DOIUrl":"10.1016/j.livres.2026.09.001","url":null,"abstract":"<div><div>Liver fibrosis, marked by excessive deposition of extracellular matrix (ECM), is a critical precursor to cirrhosis, liver failure, and hepatocellular carcinoma. Accumulating evidence highlights that cellular senescence, characterized by stable cell-cycle arrest and senescence-associated secretory phenotypes (SASPs), is a key regulator of the fibrotic process. This review systematically dissects the context-dependent roles of senescent cells in liver fibrosis, with a focus on hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells, and natural killer (NK) cells. Distinct populations of senescent cells emerge sequentially during different stages of fibrosis, exhibiting divergent kinetics and functional effects. The SASP, a dynamic cocktail composed of cytokines, chemokines, and proteases, remodels the intrahepatic microenvironment through immune cell recruitment, regulation of cell function, and modulation of ECM turnover. These effects vary depending on their molecular composition and disease context. Furthermore, we discuss emerging senescence-targeted therapeutic strategies to restore liver homeostasis. In-depth understanding of the cell-type and stage-specific roles of senescence in fibrosis provides a molecular foundation for translating senescence-targeted strategies into clinical precision antifibrotic therapies.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 210-219"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of mesenchymal stem cells on the coagulation mechanism in patients with liver cirrhosis: A review and prospects","authors":"Wanyuan Xiong,&nbsp;Zhongxia Yang,&nbsp;Zibing Qian,&nbsp;Xuebin Peng,&nbsp;Ying Li,&nbsp;Xiaorong Mao","doi":"10.1016/j.livres.2026.08.003","DOIUrl":"10.1016/j.livres.2026.08.003","url":null,"abstract":"<div><div>Cirrhosis, characterized by extensive liver fibrosis and architectural distortion, is commonly associated with coagulation disorders that increase the risk of both bleeding and thrombosis. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for liver diseases, including cirrhosis, due to their regenerative and immunomodulatory properties. This review delves into the intricate relationship between MSCs and the coagulation system in cirrhotic patients, examining the impact on platelet dysfunction, coagulation factor synthesis, endothelial dysfunction, and fibrinolysis. The review highlights MSCs’ multilineage differentiation potential and their ability to secrete both procoagulant and anticoagulant factors, which are crucial in the context of liver disease. Clinical and preclinical findings on the effects of MSC therapy on coagulation are reviewed, along with safety and risk assessments. This review highlights the promising potential of MSCs in alleviating cirrhosis-associated coagulopathy, while identifying key challenges that must be addressed to advance clinical translation. Further research is therefore warranted to elucidate the underlying mechanisms and to optimize therapeutic strategies for clinical application.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 220-230"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence in hepatocellular carcinoma diagnosis and AI-assisted treatment support: Current landscape and future directions","authors":"Quan-Kai Lei,&nbsp;Tong-Xv Wu,&nbsp;Chu-Long Zhang,&nbsp;Yun-Wen Zheng","doi":"10.1016/j.livres.2026.08.001","DOIUrl":"10.1016/j.livres.2026.08.001","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains challenging to diagnose and manage, particularly at an early stage when curative treatment is most feasible. Artificial intelligence (AI) offers tools for integrating histopathology, radiology, laboratory testing, demographics, and electronic health records, while also creating opportunities for clinician-supervised AI-assisted procedural support. Deep learning applied to digitized pathology slides can support tumor subtype classification, grading, and microvascular invasion assessment. AI-driven imaging methods may support liver and lesion segmentation, small-nodule detection in cirrhotic livers, and non-invasive risk stratification when combined with radiomics and clinical variables. Emerging foundation models, large language models (LLMs), and agentic approaches may help structure evidence, summarize longitudinal records, and support guideline-aligned decision workflows. In AI-assisted treatment-support settings, robotic surgery, endoscopic platforms, and image-guided interventions should be viewed as environments for AI-assisted planning, navigation, documentation, and quality control rather than autonomous treatment systems. Most evidence remains retrospective, single-center, and vulnerable to domain shift. Other limitations include LLM/agentic reliability failures, limited interpretability, privacy constraints, computational burden, incomplete workflow integration, workforce readiness gaps, and uncertain clinical benefit. Future progress will require diverse multimodal datasets, prospective multicenter validation, explainable and lightweight algorithms, standardized data alignment, rigorous governance, patient-centered workflow implementation, staff training, and careful separation of technical feasibility from clinically meaningful outcomes. Responsibly deployed AI may support diagnostic consistency, workflow efficiency, and human–AI collaboration in HCC care.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 189-209"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The changing etiology of liver cancer: A comparative study of global and Chinese burden trends from hepatitis dominance to metabolic risks (1990–2021) and forecasts to 2035","authors":"Xue Zhou,&nbsp;Mingle Huang,&nbsp;Xiaofen Li,&nbsp;Minjie Zhao,&nbsp;Moushen Tang","doi":"10.1016/j.livres.2026.07.001","DOIUrl":"10.1016/j.livres.2026.07.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and aims&lt;/h3&gt;&lt;div&gt;Liver cancer remains a major global health burden with a complex and shifting epidemiology. While viral hepatitis continues to drive significant morbidity, metabolic risk factors are increasingly contributing to the incidence of liver cancer. Utilizing data from the Global Burden of Disease (GBD) Study 2021, this analysis examines China’s incidence, prevalence, and age-standardized disability-adjusted life year (DALY) rates for liver cancer from 1990 to 2021, comparing these trajectories against global and regional patterns. This study further analyzed the correlations between liver cancer burden and socioeconomic development, aiming to provide evidence for targeted intervention strategies and health policy formulation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This study utilized data from the Global Burden of Disease Study 2021 to analyze the burden of liver cancer from 1990 to 2021 across 204 countries and territories. Standardized methodologies were used to estimate prevalence, incidence and DALYs. The Socio-demographic index (SDI) was applied to evaluate Socioeconomic disparities. Joinpoint regression was employed to analyze temporal trends, and age-period-cohort modeling was applied to estimate drivers of disease burden. Age-standardized rates were projected to 2035 using statistical modeling techniques.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Globally, the absolute number of liver cancer cases increased continuously, whereas age-standardized rates declined from 1990 to 2021. Prevalent cases increased by 113.7% (from 345,912.7 to 739,299.5), incident cases increased by 116.2% (from 244,689.4 to 529,202.5), and total DALYs grew by 70.6% (from 7,553,666.8 to 12,887,652.4); the age-standardized DALY rate (ASDR) declined with an estimated annual percentage change (EAPC) of −0.6 (95% CI –0.72 to −0.48). Hepatitis B-related DALYs decreased significantly, while non-alcoholic steatohepatitis (NASH) and alcohol-related cases increased. China achieved marked reductions in age-standardized rates: the age-standardized incidence rate (ASIR) decreased from 10.6 to 9.5 per 100,000 (EAPC –0.28, 95% CI –0.42 to −0.13), and the ASDR fell from 334.5 to 239.9 per 100,000 (EAPC –1.16, 95% CI –1.34 to −0.98), especially in hepatitis B, though metabolic-related burdens grew. Prevalent cases in China doubled (from 132,779.2 to 265,539.4) and incident cases rose by 104.0% (from 96,434.3 to 196,636.6). Gender and age disparities were evident, with males and older adults bearing higher burdens. High-income regions saw rising metabolic-related rates, whereas low- and middle-income areas faced persistent viral hepatitis burdens. Projections suggest a continued rise in metabolic-related liver cancer globally, with NASH-related rates accelerating fastest in China, underscoring the need for dual preventive strategies targeting both infection and lifestyle factors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The global burden of liver cancer is u","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 231-244"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond symptom relief: The promise of Linerixibat as a mechanism-based therapy for cholestatic pruritus in primary biliary cholangitis","authors":"Muhammad Hamza Ameer,&nbsp;Muhammad Areeb ul Haq,&nbsp;Menahal Naeem,&nbsp;Abeer Zia,&nbsp;Amna Siddique","doi":"10.1016/j.livres.2026.07.002","DOIUrl":"10.1016/j.livres.2026.07.002","url":null,"abstract":"","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 260-262"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MND1 protein mediates DNA damage repair and is a promising novel therapeutic target in hepatocellular carcinoma","authors":"Cheng Wang,&nbsp;Minghua Hu,&nbsp;Wanyu Xia,&nbsp;Qian Zheng,&nbsp;Chengfei Zhang,&nbsp;Ruoyu Shi,&nbsp;Chengsong Cao,&nbsp;Hongping Xia,&nbsp;Chengyun Yao","doi":"10.1016/j.livres.2026.08.002","DOIUrl":"10.1016/j.livres.2026.08.002","url":null,"abstract":"<div><h3>Background and aims</h3><div>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need to identify novel therapeutic targets. Bioinformatic analysis initially identified meiotic nuclear division 1 (<em>MND1</em>) as a differentially expressed gene in HCC, with significant associations to DNA damage repair pathways, suggesting its potential functional relevance in hepatocarcinogenesis. Based on these findings, this study aims to systematically characterize the expression profile of MND1 in HCC and to further elucidate its biological functions as well as the underlying molecular mechanisms driving HCC progression.</div></div><div><h3>Methods</h3><div>The expression profile of MND1 was validated using data from public databases along with 22 paired clinical HCC specimens. The functional roles of MND1 were investigated through <em>in vitro</em> assays (CCK-8, Transwell, and flow cytometry) and <em>in vivo</em> subcutaneous/orthotopic xenograft mouse models. Mechanistically, co-immunoprecipitation (Co-IP) coupled with mass spectrometry, immunofluorescence, and rescue experiments were applied to identify interacting proteins and to elucidate the underlying molecular pathways.</div></div><div><h3>Results</h3><div>Multi-omics analysis and clinical validation revealed that MND1 is overexpressed in HCC tissues and significantly correlates with poor prognosis. Comprehensive <em>in vitro</em> and <em>in vivo</em> functional studies further demonstrated that MND1 drives HCC progression by regulating tumor cell proliferation, migration, and invasion. Mechanistically, we uncovered a close functional association between MND1 and TRIM28, which promotes genomic instability by enhancing the activity of the DNA damage response (DDR) pathway.</div></div><div><h3>Conclusions</h3><div>These findings suggest that MND1 may serve as both a potential molecular marker and an oncogenic contributor in HCC. Importantly, the newly identified MND1–TRIM28–DDR regulatory axis offers a promising rationale for the development of targeted therapeutic strategies.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 3","pages":"Pages 245-259"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-coding RNA networks in metabolic dysfunction-associated steatotic liver disease: Mechanisms and therapeutic perspectives","authors":"Ruizhe Ren,&nbsp;Siying Ren,&nbsp;Yihan Xu,&nbsp;Xiao Liang,&nbsp;Xiyang Wei","doi":"10.1016/j.livres.2026.05.002","DOIUrl":"10.1016/j.livres.2026.05.002","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disorder worldwide, characterized by complex molecular regulatory networks driving its pathogenesis. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), serve as critical regulators of gene expression and have been increasingly recognized for their pivotal roles in MASLD development. Rather than functioning in isolation, these ncRNAs form intricate regulatory networks that integrate and amplify disease signals across multiple cellular compartments and pathological stages. This review provides a comprehensive overview of how these ncRNA networks orchestrate MASLD progression, focusing on their roles in metabolic dysregulation, inflammation, and fibrosis. We further evaluate the diagnostic potential of circulating ncRNAs as stable, non-invasive biomarkers for disease stratification and monitoring, and discuss emerging therapeutic strategies targeting ncRNAs, including antisense oligonucleotides, synthetic mimics, and advanced delivery platforms such as lipid nanoparticles and engineered exosomes. Despite significant progress, challenges related to delivery efficiency, tissue specificity, and safety remain barriers to clinical translation. By synthesizing current knowledge of ncRNA networks in MASLD and highlighting opportunities for therapeutic intervention, this review provides a roadmap for translating ncRNAs into clinical applications for this increasingly prevalent metabolic liver disease.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 2","pages":"Pages 151-165"},"PeriodicalIF":2.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13324203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From bench to bedside: Molecular mechanisms, diagnostic tools, and therapeutic strategies in liver fibrosis","authors":"Zhen Yang,&nbsp;Weizhao Tong,&nbsp;Kanglong Zhang,&nbsp;Guoxin Hu","doi":"10.1016/j.livres.2026.03.001","DOIUrl":"10.1016/j.livres.2026.03.001","url":null,"abstract":"<div><div>Liver fibrosis is a key pathological process in the progression of chronic liver disease toward cirrhosis and liver failure. The development of liver fibrosis is closely related to a variety of etiologies, including alcoholic hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, and drug-induced liver injury. Although advances in antiviral therapies for hepatitis B have contributed to a decline in its incidence, other etiologies such as MASLD and alcoholic hepatitis are becoming the main drivers for liver fibrosis. Currently, the management of liver fibrosis primarily focuses on controlling the underlying causes of liver fibrosis, including antiviral therapy and the cessation of alcohol or drug exposure. However, effective therapeutic options for advanced fibrosis remain limited, resulting in severe complications such as hepatic encephalopathy and portal hypertension, which markedly increase patient mortality and socioeconomic burden. Therefore, early diagnosis and timely intervention for liver fibrosis are essential to prevent disease progression. With the ongoing advancement of modern molecular biology technologies, our understanding of the pathogenesis and pathophysiology of liver fibrosis continues to deepen. In this review, we summarize the molecular mechanisms, diagnostic approaches, current treatments, and potential therapeutic targets for liver fibrosis.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 2","pages":"Pages 133-150"},"PeriodicalIF":2.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13324216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARα activation alleviates lithocholic acid-induced liver injury by inhibiting pyroptosis","authors":"Hang-Fei Liang,&nbsp;Chuo-Ying Mai,&nbsp;Xuan Li,&nbsp;Jia-Ning Tian,&nbsp;Hai-Guo Su,&nbsp;Min Huang,&nbsp;Jian-Hong Fang,&nbsp;Hai-Tao Wang,&nbsp;Xiao Yang,&nbsp;Hui-Chang Bi","doi":"10.1016/j.livres.2026.05.003","DOIUrl":"10.1016/j.livres.2026.05.003","url":null,"abstract":"<div><h3>Background and aims</h3><div>The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown.</div></div><div><h3>Methods</h3><div>The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation.</div></div><div><h3>Results</h3><div>Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways.</div></div><div><h3>Conclusions</h3><div>PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 2","pages":"Pages 177-188"},"PeriodicalIF":2.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13324120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kupffer cells: Orchestrators of liver physiology","authors":"Qin Cai ,&nbsp;Yusi Chen ,&nbsp;Li Tang","doi":"10.1016/j.livres.2026.01.004","DOIUrl":"10.1016/j.livres.2026.01.004","url":null,"abstract":"<div><div>As the central metabolic organ, the liver coordinates fundamental biological processes through its specialized cellular architecture and regulatory networks, encompassing metabolism, immunity, and regeneration. Kupffer cells (KCs), the liver-resident macrophages, exhibit functional heterogeneity beyond classical polarization paradigms. Currently, multiple classification systems for KCs have been established utilizing distinct surface markers. However, there is no systematic theoretical framework for the classification of KCs. The strategic positioning of KCs within the hepatic Disse space enables intricate intercellular communication networks with neighboring hepatocytes for coordinated physiological regulation. Their functional plasticity critically regulates systemic iron and metabolic homeostasis, with KC-driven metabolic reprogramming directly influencing hepatic pathophysiology. Furtherly, KC activity shows spatiotemporal regulation by circadian rhythms and nutrient signals, reshaping the liver microenvironment to affect function. This review summarizes advances in liver macrophage biology, highlighting the classification challenges of KCs and their roles in hepatic physiology. Additionally, we discuss how circadian rhythms, aging, diet, and exercise dynamically influence KC functionality, which provides a framework to interpret their regulatory logic and dysfunction in disease.</div></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"10 2","pages":"Pages 99-108"},"PeriodicalIF":2.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}