Zhou XD, Chen QF, Fan QY
… +41 more, Kim SU, Yip TC, Petta S, Nakajima A, Tsochatzis E, Boursier J, Bugianesi E, Hagström H, Chan WK, Romero-Gomez M, Calleja JL, de Lédinghen V, Castéra L, Sanyal AJ, Goh GB, Newsome PN, Fan JG, Lai M, Fournier-Poizat C, Lee HW, Wong GL, Armandi A, Shang Y, Pennisi G, Llop E, Yoneda M, de Saint-Loup M, Canivet CM, Carrillo-Fernandez P, Lara-Romero C, Gallego-Durán R, Asgharpour A, Teh KK, Sau-Wai Chan M, Lin H, Liu WY, Targher G, Byrne CD, Wong VW, Zheng MH, and the VCTE-Prognosis Study Group
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic l...BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). OBJECTIVE: We investigated the relationships between CKM stages and liver fibrosis severity, progression, and the risk of liver-related events (LREs) in MASLD. DESIGN: Patients with MASLD from the VCTE-Prognosis cohort were stratified according to CKM stages. Outcomes included the prevalence of advanced liver fibrosis (LSM ≥10 kPa), liver stiffness progression (≥20% increase and Baveno category upshift), and incident LREs. Associations were assessed using multivariable logistic regression and Cox proportional hazards models. RESULTS: Among 12,097 patients with MASLD, the prevalence of advanced liver fibrosis increased across CKM stages at baseline: 9.6% (CKM stage 0-1), 18.0% (CKM stage 2), and 31.6% (CKM stage 3-4). CKM stage 2 (adjusted OR=1.663, 95% CI 1.444-1.915) and CKM stage 3-4 (adjusted OR=2.575, 95% CI 2.109-3.144) were independently associated with advanced fibrosis. During a 4.5-year median follow-up, 716 patients (6.1%) experienced progression of liver stiffness, and 352 patients (1.7%) developed LRE. Compared with CKM stage 0-1, the risk of liver stiffness progression was higher in CKM stage 2 (adjusted HR=1.321, 95% CI 1.050-1.662; p =0.018) and CKM stage 3-4 (adjusted HR=1.767, 95% CI 1.339-2.330; p <0.001). In contrast, only CKM stage 3-4 were significantly associated with an increased risk of LREs (adjusted HR=1.975, 95% CI 1.245-3.133; p =0.004). CONCLUSIONS: CKM stages are independently associated with the severity and progression of liver fibrosis in MASLD. CKM stage 2 significantly increases liver stiffness progression without excess LRE risk, while CKM stage 3-4 confer the highest risk for liver-related outcomes.
BACKGROUND AND AIMS: Hepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are...BACKGROUND AND AIMS: Hepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are central to understanding its pathogenesis. This study aimed to elucidate how macrophage lipid metabolism mediated by CD36 regulates immune function and fibrosis development. APPROACH AND RESULTS: We demonstrated that macrophages engulf lipids secreted by hepatic stellate cells (HSCs) via the CD36 receptor, resulting in enhanced lipid peroxidation, ferroptosis, and diminished antigen-presenting capacity, thereby impairing CD8 + T cell function. Conversely, CD36 deficiency restored antigen presentation through activation of the cGAS-STING pathway. Single-cell RNA sequencing further revealed that loss of CD36 in myeloid cells upregulated MHC-I-related gene expression in macrophages and promoted CD8 + T cell activation within the fibrotic liver microenvironment. Macrophage-specific CD36 knockout protected mice from fibrosis progression. In patients with liver cirrhosis, histological and serological analyses showed elevated CD36 expression, underscoring its clinical relevance. CONCLUSIONS: CD36-driven lipid uptake induces macrophage ferroptosis and impairs adaptive immunity. Targeting CD36 restores macrophage antigen-presenting function and enhances CD8 + T cell activation, identifying CD36 as a potential therapeutic target for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry10830).
In oncology, the radiological assessment of treatment response is crucial for predicting therapeutic efficacy in terms of survival, both in clinical trials and daily practice. However, this fundamental principle is often...In oncology, the radiological assessment of treatment response is crucial for predicting therapeutic efficacy in terms of survival, both in clinical trials and daily practice. However, this fundamental principle is often challenged in the context of HCC, where cirrhosis-related phenomena complicate radiological evaluation and impact patient prognosis beyond the oncological disease itself. In addition, the introduction of new therapeutic agents into the rapidly evolving landscape of systemic treatment further complicates this task, raising significant concerns about the validity of commonly used response criteria in this setting. Here, we aim to provide a critical view of tumor response evaluation to systemic therapy in HCC. First, we review the main treatment response criteria to systemic therapy, emphasizing the differences and limitations of RECIST 1.1 and mRECIST. Second, we delve into the challenges of radiological evaluation both in clinical trials and daily practice, with a particular focus on emerging approaches currently under investigation, such as immunotherapy-based downstaging and conversion therapy. Finally, we discuss emerging trends and future directions in radiological assessment techniques, including 3D imaging, artificial intelligence, and radiomics, and their potential impact on refining treatment evaluation in the era of precision oncology.
BACKGROUND AND AIMS: Macrovascular invasion (MaVI) defines advanced-stage hepatocellular carcinoma (HCC) and typically mandates systemic therapy, yet some guidelines advocate surgery or locoregional approaches. We conduc...BACKGROUND AND AIMS: Macrovascular invasion (MaVI) defines advanced-stage hepatocellular carcinoma (HCC) and typically mandates systemic therapy, yet some guidelines advocate surgery or locoregional approaches. We conducted a systematic review and meta-analysis of overall survival (OS) in HCC with MaVI treated with approaches other than systemic therapy, enforcing stringent inclusion criteria to exclude studies lacking a minimal prognostic dataset and to improve cohort comparability. APPROACH AND RESULTS: PRISMA-guided methods were used (CRD420251051847). PubMed was searched (January 2008 to November 2024). Eligible studies reported OS for HCC with MaVI and provided baseline performance status and liver function; studies without adequate prognostic information were excluded. Data on OS at 1, 2, 3, and 5 years were extracted, and heterogeneity was assessed. Seventy-three studies met criteria (104 treatment arms; 10,329 patients). Despite a rigorous identification process, substantial heterogeneity persisted for most modalities ( I2 >80%), precluding robust pooling. Transarterial radioembolization (TARE) monotherapy was the only treatment with low heterogeneity ( I2 =0%) and showed a pooled 1-year OS of 34% (95% CI: 20%-48%). Apparent advantages of sequential strategies likely reflected confounding by indication and immortal-time bias, as only patients who lived long enough and were sufficiently fit proceeded through the full sequence. Data completeness declined beyond 12 months (missing OS: 0% at 1 y; 17.3% at 2 y; 32.7% at 3 y; 70.2% at 5 y). CONCLUSIONS: In HCC with MaVI, 1-year OS is the most comparable endpoint across modalities. This analysis identifies TARE as the only consistently reproducible option, showing a 1-year survival of 34%. In contrast, surgery and sequential therapies remain confounded by substantial heterogeneity. Accordingly, stratified head-to-head trials comparing alternative modalities against immunotherapy are warranted.
Ruan Q, Chen T, Kim M
… +13 more, Yang H, Sinha D, He Y, Burke L, Wickramasuriya L, Cao L, Yan W, Hooper J, Wang H, Bridle K, Chandra J, Crawford D, Liang X
BACKGROUND AND AIMS: The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemot...BACKGROUND AND AIMS: The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. APPROACH AND RESULTS: CAF subpopulations and alpha-smooth muscle actin expression were analyzed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. Alpha-smooth muscle actin expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. In vitro experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumor cells of hepatocellular carcinoma (HCC) and biliary tract cancer origin. RNA sequencing revealed that the PI3K signaling pathway underlined the activation of HSCs in response to excessive ROS. This was further analyzed in HCC mouse models on nonfibrotic and fibrotic livers. A 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumors following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumor burden in murine HCC models. CONCLUSIONS: This study demonstrates the role of platinum-based chemotherapy in HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.
BACKGROUND AND AIMS: Liver cirrhosis, a leading global cause of mortality, is marked by progressive fibrosis and immune dysregulation. Tissue-resident memory T (T RM ) cells, particularly γδ T cells, are emerging as crit...BACKGROUND AND AIMS: Liver cirrhosis, a leading global cause of mortality, is marked by progressive fibrosis and immune dysregulation. Tissue-resident memory T (T RM ) cells, particularly γδ T cells, are emerging as critical regulators of hepatic immunity; however, their role in fibrogenesis remains poorly understood. APPROACH AND RESULTS: Through single-cell RNA sequencing and flow cytometry, we show that CD69 + CXCR6 + γδ T cells are enriched in healthy livers and produce IFN-γ and IL-2 but are significantly depleted in cirrhotic tissue, correlating with disease severity. In a murine fibrosis model, CXCR6 + γδ T cells limited fibrosis progression by inducing hepatic stellate cell apoptosis via FasL-Fas signaling. Adoptive transfer of CXCR6 + γδ T cells significantly mitigated fibrosis, whereas CXCR6 - γδ T cells showed no such effect. CONCLUSIONS: Liver-resident CD69 + CXCR6 + γδ T cells constitute a protective immune subset that limits fibrosis development and progression. Enhancing the function or abundance of this population may offer a promising immunotherapeutic strategy for liver cirrhosis.
Xun Z, Wang H, Xuan Z
… +23 more, Xiong K, Zhang N, Long J, Sun H, Li Y, Zhu C, Piao M, Zhang T, Zhang L, Li S, Li C, Li J, Sun B, Zhou Z, Wang S, Huang Z, Liu K, Tan Y, Shi X, Yang X, Wang H, Lu L, Zhao H
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a highly metastatic tumor type, and iCCA with intrahepatic metastasis is associated with poor prognosis. Previous studies have confirmed that the tumor micro...BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a highly metastatic tumor type, and iCCA with intrahepatic metastasis is associated with poor prognosis. Previous studies have confirmed that the tumor microenvironment (TME) is closely related to tumor metastasis. However, the state of the TME during iCCA liver metastasis remains unknown. APPROACH AND RESULTS: We profiled 28 specimens from 16 patients with iCCA (with and without intrahepatic metastasis) using integrated single-cell and spatial transcriptomics, bulk RNA sequencing, whole-exome sequencing, and in vivo and in vitro functional experiments to characterize the specific TME changes during iCCA liver metastasis. We identified the metastatic tumor cells, COL3A1 + epithelial cells, and revealed that COL3A1 + epithelial cells-endothelial-to-mesenchymal transition cells crosstalk promoted tumor invasion by inducing mesenchymal transformation of endothelial cells, while COL3A1 + epithelial cells-VEGFA + CCL4 + neutrophils crosstalk promoted tumor colonization by forming neutrophil extracellular traps. CONCLUSIONS: We revealed the key biological mechanisms involved in the invasion and colonization phases of iCCA liver metastasis. Moreover, we provide valuable data for understanding iCCA liver metastasis and a possible avenue for the treatment of advanced iCCA.