The pre-metastatic niche constructed by cancer-associated fibroblasts (CAFs) plays a key role in the hypoxic tumor microenvironment (TME), promoting hepatocellular carcinoma (HCC) metastasis. Integrin, which is involved in cell-to-cell or cell-to-matrix interactions and TME regulation, affects tumor metastasis. However, the complex interactions between integrin-mediated HCC cells and CAFs remain unclear. Co-culture experiments were used to assess the behaviors of HCC cells and CAFs, demonstrating HCC metastatic traits and CAFs activation in vitro. Transcriptome sequencing analysis and molecular detection identified key genes, with overexpression and knockdown experiments further confirming their roles in HCC progression. Xenograft models validated these findings in vivo. We showed that HCC cells induced the conversion of normal hepatic stellate cells (HSCs) into CAFs and recruit additional CAFs, driven by lactate produced by HCC. Integrin beta 4 (ITGB4) was identified as a key gene in the process. Inhibiting ITGB4 reduced lactate secretion, reversed CAFs activation and recruitment, and decreased HCC metastasis, while overexpressing ITGB4 significantly enhanced these malignant phenotypes. ITGB4 influences glycolysis and HCC metastasis through the AKT/HK2 signaling pathway, and CAFs activation and recruitment through the TGF-β/Smads signaling pathway. Compared to tumors derived from control cells, ITGB4-knockdown tumors showed fewer and smaller intrahepatic metastatic nodules, reduced lactate production and CAFs formation, along with inhibition of AKT/HK2 and TGF-β/Smads signaling pathways. Our findings highlighted the impact of hypoxia on HCC progression, revealing the roles of ITGB4-mediated glycolysis and lactate-induced CAFs in the pre-metastatic niche on HCC metastasis.

Several inflammatory indicators have been reported to have predictive value in many types of malignant cancer. This research was aimed to explore the ability of the monocyte-to-lymphocyte ratio (MLR) to predict prognosis in patients with intrahepatic cholangiocarcinoma (ICC) who subjected to curative hepatectomy. This retrospective analysis included 196 patients with ICC who underwent curative hepatectomy between May 2018 and April 2023. The predictive abilities of the preoperative MLR in assessing overall survival (OS) and disease-free survival (DFS) in those patients were compared with other inflammation-based scores, including monocyte-to-white ratio, neutrophil-to-lymphocyte ratio, neutrophil-to-white ratio, platelet-to-lymphocyte ratio, platelet-to-white ratio, and systemic immune-inflammation index, as well as tumor markers, like carcinoembryonic antigen (CEA) and carbohydrate antigen 19 − 9 (CA19-9). The area under the time-dependent receiver operating characteristic curve indicated that the preoperative MLR had higher predictive efficiency in contrast with other inflammation-based scores and tumor markers in assessing OS and DFS. Stratifying patients according to the optimal cut-off value for the preoperative MLR, the data showed that both OS and DFS in the high MLR group were significantly worse than those in the low MLR group (p < 0.05 for all). Univariable and multivariable Cox analyses revealed that the preoperative MLR was an independent risk factor for OS and DFS in patients with ICC. In addition to predicting OS in patients with high CEA levels and predicting DFS in patients with high CA19-9 levels, patients with different CEA and CA19-9 levels were divided into completely different OS and DFS subgroups based on the risk stratification of the preoperative MLR. Our results demonstrated that the preoperative MLR was a good prognosis indicator to predict DFS and OS following curative hepatectomy in patients with ICC.

Objective: Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH. Backgrounds: Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC. Methods: Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram. Results: This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR. Conclusion: This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.

Background and Aims: Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. Approach and Result: A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. “Loss-of-function” experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA^−/−) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA^−/− mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA^−/− mice with hepatic IRI. Furthermore, the TGF-β1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. Conclusions: These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.

Semen Persicae, a traditional Chinese medicine, has shown potential in alleviating metabolic dysfunction-associated fatty liver disease (MAFLD). However, the complexity of components limits its clinical application. To identify the key active component of Semen Persicae responsible for attenuating MAFLD and to elucidate the underlying mechanism. The chemical components of Semen Persicae were characterized using mass spectrometry. A high-fat diet-induced MAFLD mouse model and primary liver sinusoidal endothelial cells (LSECs) were employed. Liver histopathology was used to evaluate the efficacy and safety of amygdalin (Amy). Single-cell RNA sequencing (scRNA-seq) and untargeted metabolomics analyses of mouse livers were integrated to preliminarily investigate the mechanism. Scanning electron microscopy (SEM) and assessment of fenestration markers were used to evaluate the fenestrae status of LSECs. Cytoplasmic calcium ion (Ca2+) staining, along with measurements of prostaglandin E2 (PGE2) and inositol triphosphate (IP3) levels, was applied to assess Ca2+ overload in LSECs. Mass spectrometry identified Amy as a major component of Semen Persicae. In a diet-induced MAFLD mouse model, Amy treatment dose-dependently attenuated disease progression, showing therapeutic efficacy comparable to liraglutide, with marked improvements in systemic metabolic parameters and significant reductions in hepatic steatosis and inflammation. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the most responsive cell population, with Amy markedly reducing the abundance of capillarized LSEC states. Ultrastructural analyses further demonstrated that the reduced fenestration density observed in MAFLD was substantially restored following Amy treatment. Integrated transcriptomic and metabolomic analyses revealed that arachidonic acid metabolism and endoplasmic reticulum Ca²⁺ signaling were prominently affected by Amy. In vitro experiments further confirmed that Amy reduced elevated PGE2 and IP3 levels, thereby suppressing excessive endoplasmic reticulum Ca²⁺ release. Amy effectively ameliorates LSECs defenestration by reversing IP3-induced cytoplasmic Ca2+ overload, highlighting its potential as a plant-derived therapeutic candidate for MAFLD.

Hepatocellular carcinoma (HCC), a highly malignant digestive system tumor, poses substantial challenges due to its intricate underlying causes and pronounced post-surgery recurrence. Consequently, the prognosis for HCC remains notably unfavorable. The endorsement of sorafenib and PD-L1 inhibitors for HCC signifies the onset of a new era embracing immunotherapy and targeted treatment approaches for this condition. Hence, comprehending the mechanisms underpinning targeted immune combination therapy has become exceedingly vital for the prospective management of HCC patients. This article initially presents a triumphant instance of curative treatment involving the combination of TKI and PD-1 inhibitor subsequent to liver resection, targeting an advanced stage HCC as classified by the BCLC staging system. The case patient carries a decade-long history of hepatitis B, having undergone a regimen of 20 courses of treatments involving apatinib and camrelizumab. Throughout the treatment period, no occurrences of grade 3 or 4 adverse events (AE) were noted. Subsequently, the patient underwent a left hepatectomy. Following the hepatectomy, their serum AFP levels have consistently remained within normal limits, and CT imaging has indicated the absence of tumor recurrence over a span of 36 months. The patient had been reviewed on time for two years after the operation. The last time a CT was performed for this patient in our hospital was 7 May 2021, and no new tumors were found. Follow-up is still ongoing. When applying combined targeted immune transformation therapy using TKI and ICI for a patient with BCLC advanced stage HCC, apatinib treatment serves a dual purpose. It inhibits the survival and angiogenesis of tumor cells, while also enhancing the efficacy of camrelizumab in obstructing the interaction between PD-1 and PD-L1. This restoration of T cell cytotoxicity subsequently facilitates the elimination of tumor cells, leading to an enhanced anticancer effect.