BACKGROUND The diagnostic value of serum chitinase-3-like protein 1 (CHI3L1) in liver fibrosis and cirrhosis, as well as its prognostic significance in hepatocellular carcinoma (HCC), remains incompletely understood. AIM To assess the diagnostic value of CHI3L1 for liver cirrhosis in liver disease patients and its prognostic significance in HCC. METHODS A retrospective study was conducted at a tertiary hospital to measure serum CHI3L1 levels in 551 patients from different cohorts (viral/non-viral hepatitis, cirrhosis, HCC, post-radical hepatectomy HCC, and HCC recurrence) and healthy controls using electrochemiluminescence. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of CHI3L1, and its correlation with liver stiffness measurement (LSM) and the fibrosis-4 index (FIB-4) was analyzed. RESULTS Serum CHI3L1 levels were significantly higher in the cirrhosis, HCC, post-radical hepatectomy HCC, and HCC recurrence groups than in the control group (all P < 0.05). The cirrhosis group had higher serum CHI3L1 levels than the viral hepatitis and non-viral hepatitis groups (both P < 0.01), and the HCC group had higher serum CHI3L1 levels than the post-radical hepatectomy HCC group (P < 0.001). The areas under the ROC curve of CHI3L1 for diagnosing cirrhosis, HCC, and HCC recurrence were 0.874, 0.858, and 0.723, respectively. CHI3L1 levels were positively correlated with LSM (r = 0.424, P < 0.001) and FIB-4 (r = 0.370, P < 0.001). CHI3L1 levels differed significantly between fibrosis grades F3 and F4 (P < 0.01). CONCLUSION Serum CHI3L1 levels hold significant diagnostic value for liver fibrosis, cirrhosis, and HCC, serving as an effective non-invasive marker for these conditions as well as HCC recurrence.

Background and Aims:Extrahepatic cancers have been recognized as a significant outcome of metabolic dysfunction-associated steatotic liver disease (MASLD), which involves five cardiometabolic risk factors, including hypertension, and is associated with the tumorigenesis of several cancers or with anti-cancer treatment. We aimed to investigate the association between hypertension, liver fibrosis, and extrahepatic cancers in the MASLD population. Methods:This multicenter cross-sectional study was based on a MASLD population from hospital-based databases across 11 centers nationwide in China, according to MASLD diagnostic criteria identified using keywords and ICD-10 codes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between risk factors and extrahepatic cancers. Results:A total of 103,652 individuals with MASLD were identified, among whom 6,605 were diagnosed with extrahepatic cancers. The primary outcome revealed that hypertension was significantly associated with extrahepatic cancers (OR 1.14, 95% CI: 1.08-1.21), and its combination with hyperglycemia further increased this association (OR 1.36, 95% CI: 1.22-1.51). Risk factors for extrahepatic cancers included being over 40 years of age and female sex. Conversely, certain metabolism-based treatments were found to have potentially protective effects, including angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, fibrates, GLP-1 receptor agonists, and thiazolidinediones. After adjusting for confounding factors, the fibrosis-4 (FIB-4) score was associated with extrahepatic cancers. In the hypertension subgroup, FIB-4 scores of 1.30-2.66, 2.67-3.47, and ≥ 3.48 were associated with extrahepatic cancers in individuals aged 35-64 years, consistent with findings in those aged ≥ 65 years of age with FIB-4 ≥ 2. Conclusions:Hypertension combined with liver fibrosis is associated with extrahepatic cancers in patients with MASLD.

Recurrence rate remains unsatisfactory among surgical resected hepatocellular carcinoma (HCC) patients with radical resection intention, and effective surveillance methods are lacking for post-operative recurrence. 436 HCC patients were selected for ultimate analyses. Significant features were extracted on favorable regions of interest (ROIs) of contrast-enhanced CT (CECT) and selected by least absolute shrinkage and selection operator (LASSO) method to construct radiomics signature. A novel CT radiomics-clinicopathological prediction model was constructed to evaluate 2-year recurrence-free survival (RFS) of resected HCC. Model discrimination was evaluated by area under the receiver operating characteristic (ROC) curve, the calibrated curves and decision curve analysis. Gene expressions of CENPA, FAM83D etc. were assessed by quantitative real-time PCR (q-PCR) for 48 randomly selected HCC patients, and correlation between radiomics signature and genomic characteristics was investigated. Radiomics signature was established based on the 20 early recurrence-related CT features. Microvascular invasion (MVI), alpha-fetoprotein (AFP), gamma-glutamyl transpeptidase to lymphocyte ratio (GLR) and radiomics signature were selected as independent predictors of early recurrence of HCC, and thereafter used to construct the novel nomogram which predicted 2-year RFS. The radiomics-clinicopathological combined model revealed favorable prediction ability with area under the ROC curve (AUC) of 0.744 and 0.821 to predict 2-year RFS in training and validation cohort. HCC patients were divided into three risk groups, with RFS difference between groups statistically significant. Similar results were observed in AFP-negative HCC cohort. Pearson correlation analyses revealed favorable relationship between radiomics signature and BCAT1 and CENPA. This study constructed a noninvasive and simple prediction model based on CT radiomics and clinical features. The novel radiomics-clinicopathological predictive model could evaluate post-operative early recurrence for HCC, and its significance remained in AFP-negative HCC.

Given the significant clinical and economic burden of metabolic dysfunction-associated steatohepatitis (MASH), there is an urgent imperative to develop effective preventive and therapeutic agents. In this study, we evaluated the preventive effects and potential mechanisms of plant-derived compounds inositols (INS) and inositol hexakisphosphate (IP6) against MASH, utilizing a mouse model induced by western diet combined with low doses of CCl4 (WD/CCl4). The results showed that pretreatment with IP6 or INS significantly reduced obesity, fibrosis and lipid accumulation, alleviated insulin resistance, and prevented hyperglycemia in MASH mice. Both IP6 and INS also alleviated free fatty acid (FFA)- induced lipid accumulation in HepG2 cells. Transcriptomics analysis of the liver revealed that IP6 and INS reversed MASH-related transcriptomic changes, suppressing the expression of pro-fibrotic, pro-inflammatory, and lipid-metabolic genes. Integrated metabolomics and lipidomics revealed that the preventive effect of IP6 and INS against MASH was mediated through the rectification of disordered glycerophospholipid metabolism. Notably, knockdown of PEMT expression abolished the inhibitory effects of IP6 and INS on lipid accumulation, as well as α-SMA and COL-1 expression, in in vitro assays. These findings provide evidence that both IP6 and INS can prevent the development of MASH by improving disorders in glycerophospholipid metabolism, at least partially through the upregulation of PEMT.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and chronic kidney disease (CKD) have shown a significant increase in comorbidity on a global scale due to the prevalence of metabolic syndrome. In 2023, a number of academic societies formally proposed the concept of MASLD, superseding the previous terminology of "non-alcoholic fatty liver disease" and "metabolic dysfunction-associated fatty liver disease". The diagnostic criteria have been revised to place greater emphasis on the association between hepatic steatosis and cardiometabolic risk factors. MASLD constitutes an independent risk factor for CKD, with this risk potentially increasing in line with the severity of fatty degeneration and the progression of hepatic fibrosis. CKD may represent a potential risk factor for the progression of fibrosis in patients with MASLD. The interaction between the two conditions may accelerate the occurrence of cardiovascular events and increase the risk of all-cause mortality. MASLD and CKD may share core pathophysiological mechanisms, including genetic variants, insulin resistance, lipid metabolism disorders, chronic inflammation, oxidative stress, and gut microbiota dysbiosis. However, the bidirectional causal relationship between the two conditions and the molecular dialogue between organs remains unclear. Furthermore, there are significant gaps in clinical prediction tools and targeted treatment strategies for comorbidities. This paper reviews common pathophysiological mechanisms in MASLD and CKD, the epidemiological and clinical evidence linking MASLD to the risk of CKD, biomarkers and clinical prediction models for coexisting conditions, and potential therapeutic strategies. Our aim is to provide a theoretical basis for early identification, mechanism exploration, and clinical treatment of comorbidities.

Background and Objectives:Liver regeneration necessitates coordinated cytoskeletal dynamics, yet the key molecular orchestrators remain incompletely defined. Intriguingly, recent studies reveal a novel role for hepatocyte-derived Igκ in promoting hepatocyte survival during liver injury. However, the precise mechanisms by which immunoglobulin κ (Igκ) governs liver regeneration and its potential as a central coordinator remain elusive. This study aims to elucidate the role of Igκ in liver regeneration following injury and to define the underlying molecular mechanisms. Methods:Igκ expression was assessed in liver biopsies from patients with drug-induced liver injury (DILI) using immunohistochemistry. To investigate its role in regeneration, hepatocyte-specific Igκ-knockout mice were subjected to partial hepatectomy (PHx) or acetaminophen (APAP)-induced acute liver injury. Functional and mechanistic studies were performed in the normal human hepatocyte cell line THLE-2 through Igκ knockdown or overexpression, combined with multi-omics profiling, immunoprecipitation, and mass spectrometry. The therapeutic potential of Igκ was validated by AAV8-mediated hepatic delivery of Igκ in knockout mice. Results:Igκ expression is significantly upregulated in both human DILI patients and murine injury models upon hepatic damage. Hepatocyte-specific Igκ deletion impaired liver regeneration, characterized by disrupted cytoskeletal organization and diminished hepatocyte proliferation. Mechanistically, Igκ directly binds to myosin light chain kinase (MYLK), shielding it from K48-linked ubiquitination and proteasomal degradation, thereby preserving cytoskeletal integrity and facilitating Yes-associated protein (YAP) nuclear translocation to activate proliferative pathways. Crucially, AAV8-mediated hepatic Igκ delivery in knockout mice rescues MYLK protein levels, restores cytoskeletal integrity, and promotes liver regeneration. Conclusions:Our study identifies Igκ as a pivotal regulator of liver regeneration by stabilizing MYLK to maintain cytoskeletal dynamics and potentiate YAP-dependent proliferative signaling, thereby proposing a potential therapeutic strategy for enhancing hepatic repair.