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.
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 pro- and anti-coagulant 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.
Background and aims 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 (MND1) 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. Methods 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 in vitro assays (CCK-8, Transwell, and flow cytometry) and in vivo 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. Results Multi-omics analysis and clinical validation revealed that MND1 is overexpressed in HCC tissues and significantly correlates with poor prognosis. Comprehensive in vitro and in vivo 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. Conclusions 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.
Background and aims: 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. Methods: 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. Results: 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. Conclusions: The global burden of liver cancer is undergoing an epidemiological transition, marked by declining viral hepatitis-related rates but rising metabolic- and alcohol-related cases. Significant reductions in age-standardized rates were observed in China, though absolute case number increased. Socioeconomic and geographic disparities persist, with high-income regions facing growing metabolic burdens. Future trends emphasize the need for integrated strategies addressing both infectious and lifestyle-related risk factors.
