BACKGROUND:Hepatocellular carcinoma (HCC), one of the most prevalent cancers worldwide, has a high mortality owing to diagnostic challenges and therapeutic resistance. Lactate metabolism and protein lactylation play key roles in HCC progression; nevertheless, their regulatory mechanisms remain poorly understood. OBJECTIVE:This study aims to elucidate how lactate metabolism and protein lactylation contribute to HCC malignant progression by integrating multi-omics data, identifying key regulatory factors and exploring therapeutic strategies targeting this pathway. DESIGN:Integrated multi-omics analysis identified AARS2-AP-2γ as a key axis in HCC. Through mechanistic studies and virtual screening, we developed kukoamine A-a targeted inhibitor delivered via nanocarriers-demonstrating significant therapeutic potential. RESULTS:AARS2 was identified as a key regulator linking lactate metabolism to HCC progression through lactylation modification. It catalyses AP-2γ lactylation at K444, enhancing TRIM28 binding to promote K63-linked ubiquitination and nuclear translocation, thereby facilitating tumour progression. The inhibitor kukoamine A disrupts AARS2-AP-2γ interaction and, when delivered via zeolitic imidazolate framework-8 nanocarriers, demonstrates improved liver targeting, potent antitumour activity and synergy with PD-1 blockade, offering new strategic avenues for HCC precision therapy. CONCLUSION:AARS2 links lactate metabolism to HCC progression via lactylation. Kukoamine A nanotherapy targeting this axis shows synergistic efficacy with immunotherapy, advancing the prospects of precision oncology.

Embolization is an effective treatment modality for intermediate- and advanced-stage Hepatocellular carcinoma (HCC). Transarterial radioembolization (TARE), which combines radiotherapy with embolization, not only induces tumor necrosis by occluding blood flow with embolic agents but also exerts local radiotherapeutic effects to damage tumor cells, thereby significantly enhancing the therapeutic efficacy of embolization. Current radiolabeled microspheres used for internal irradiation therapy in HCC have limitations, such as suboptimal embolization efficacy, a tendency for non-target embolization, an inability to track embolic agents during and after surgery, and the generation of reactive oxygen species (ROS) during radiotherapy, which can damage normal tissues. To address these issues, visualizable cationic quaternary ammonium salt-based drug-eluting microspheres capable of loading 131I and the radioprotective agent amifostine were developed. The microspheres exhibit good embolic properties and can be visualized over an extended period using CT and DSA. The microspheres, carrying a positive charge, are capable of loading amifostine via ion exchange. After loading amifostine, these microspheres can not only provide local radiotherapy within the tumor but also continuously release amifostine locally to neutralize ROS in normal liver tissue. This approach not only enhances the utilization of amifostine in vivo but also protects the liver without compromising the efficacy of TARE thereby further improving the precision of radiotherapy.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of novel therapeutic targets. The transmembrane protein MAL2 has been implicated in various cancers, but its functional role and mechanistic underpinnings in HCC are not fully understood. To comprehensively understand its role in HCC, we analyze public single-cell RNA sequencing (scRNA-seq) data and find that MAL2 is significantly enriched in malignant HCC cells. In vitro, MAL2 is stably knocked down by shRNA in Hep-3B and HCC-LM3 cell lines, and functional experiments including colony formation, EdU, transwell, and wound healing assays demonstrate that MAL2 depletion markedly suppresses proliferation, invasion, and migration of HCC cell lines. In vivo, a subcutaneous tumor model using H22 cells reveals that MAL2 knockdown inhibits tumor growth, accompanied by reduced Ki-67 level and increased apoptosis. Further analysis via mass cytometry indicates that MAL2 downregulation reshapes the immune microenvironment, notably reducing CD4 + T cells, Tregs, CD8 + T cells, and exhaustion markers (PD-L1, PD1, and TIGIT) while increasing B cells and myeloid-derived suppressor cells (MDSCs). Mechanistically, ELISA and immunofluorescence staining validate that MAL2 knockdown impairs the secretion of CCL22, a chemokine known for recruiting Tregs, leading to reduced Treg recruitment and decreased production of the immunosuppressive cytokines IL-10 and TGF-β. In conclusion, MAL2 drives HCC progression by promoting tumor cell proliferation, invasion, and immunosuppression through CCL22-mediated Treg recruitment, positioning MAL2 as a promising therapeutic target to counteract tumor growth and remodel the immunosuppressive microenvironment in HCC.

The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context. We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients. Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415–1.890; p < 0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720–0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies. Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.

Background Current liver cancer research lacks reliable in vitro models that replicate tumor pathophysiology. This study establishes primary liver cancer (PLC) organoids from three major subtypes-hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (CHC)-to enable precise diagnostics and personalized therapies through comprehensive genomic profiling. Methods Organoid cultures were generated from 11 PLC patients (5 HCC, 3 ICC, 3 CHC). Whole exome sequencing (WES), RNA-seq, and single-cell RNA-seq (scRNA-seq) were performed to analyze molecular differences. Drug screening targeting subtype-specific pathways was conducted to validate sequencing findings. Results WES and RNA-seq confirmed that organoids retained parental tumor genetics and heterogeneity, distinct from paracancerous tissues. scRNA-seq revealed distinct cell populations in HCC, ICC, and CHC organoids. Lipid metabolism was enriched in HCC organoids; tumor migration pathways were upregulated in ICC organoids; and mitochondrial function was enhanced in CHC organoids. Rosuvastatin inhibited HCC growth by targeting lipid metabolism, while pemigatinib reduced ICC malignancy by suppressing epithelial-mesenchymal transition. Regorafenib impaired mitochondrial function in CHC organoids, slowing progression. Conclusions PLC-derived organoids serve as robust tools for biomarker discovery and drug screening. scRNA-seq elucidates inter-and intra-tumoral heterogeneity, offering insights for precision therapy in liver cancer. This model advances personalized treatment strategies for diverse PLC subtypes.

Rationale: Liver regeneration is regulated by both metabolic processes and immune responses. Nonetheless, there is limited comprehension of the mechanisms involved. PINK1/Parkin-mediated mitophagy has been well documented, the role and underlying alternative mechanism of PINK1/Parkin in regulating mitochondrial metabolism during liver regeneration remains unclear. Methods: Liver tissues from mice undergoing hepatectomy were utilized to evaluate the expression levels of PINK1/Parkin. Hepatocyte-specific PINK1 knockout and transgenic mouse models were generated to investigate the impact of PINK1 on regeneration. Mass spectrometry, co-immunoprecipitation, and ubiquitination assays were performed to explore the underlying molecular mechanisms. Results: We observed PINK1/Parkin expression was markedly upregulated in hepatic tissue following liver resection. PINK1 depletion in hepatocytes caused impaired liver regeneration. Moreover, mitochondrial calcium overload was found be responsible for restricted TCA by inhibiting succinate dehydrogenase activity in PINK1 deficient hepatocytes. Interestingly, PINK1 deficiency leads to succinate accumulation and release from hepatocytes, which impairs liver regeneration by restricting macrophage pro-repair phenotypes. This effect was further confirmed by enhanced regeneration in myeloid SUCNR1 knockout mice. Mechanistically, Sigma-1 is a molecular chaperone of the endoplasmic reticulum calcium channel IP3R, which helps maintain its normal functional conformation. Parkin was able to bind Sigma-1 through its UBL domain, facilitating its k48-linked ubiquitination, which promotes Sigma-1 degradation and subsequently suppressing calcium transfer from the ER to mitochondria at the mitochondrial-associated ER membrane. Conclusions: Collectively, PINK1/Parkin signaling regulates hepatocellular mitochondrial ATP and succinate production by modulating ER-mitochondria calcium transfer to promote liver regeneration, revealing a promising therapeutic target for liver regeneration.

BACKGROUND:Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS:Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS:A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION:These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

Lactate and its mediated modification, lactylation, are receiving increasing attention in the field of tumor biology. This review provides a comprehensive overview of the mechanistic involvement of lactate and lactylation in key oncogenic processes, such as tumor initiation, proliferation, invasion, metastasis, recurrence, and drug resistance. Rather than being a passive byproduct of glycolysis, lactate actively shapes the tumor microenvironment (TME), modulates immune responses, drives metabolic adaptation, and influences epigenetic and transcriptomic regulation. Lactylation, as a novel epigenetic mechanism, links cellular metabolism with gene expression by modifying histone and nonhistone proteins, thereby regulating chromatin accessibility, immune evasion, and DNA repair. Notably, this article proposes a new perspective: lactate accumulation in certain tumors may constitute an adaptive metabolic strategy rather than a passive consequence of altered metabolism. This paradigm challenges the traditional perception of lactate as a metabolic waste, instead proposing its dual function as both a signaling molecule and a strategic modulator of tumor progression. The interplay of lactate-mediated signaling pathways, such as the PI3K/AKT, Hippo, Wnt, MAPK, and JAK/STAT pathways, further underscores the role of lactate in cancer progression. This review also explores therapeutic opportunities targeting lactate metabolism and lactylation, including inhibitors of LDH, MCTs, and lactylation-modifying enzymes, as well as the synergistic potential of combining lactate-targeted approaches with chemotherapy, immunotherapy, and targeted therapy. Overall, this review provides an integrative overview of lactate-mediated mechanisms and highlights their potential as targets for metabolism-oriented therapeutic interventions in oncology.

BACKGROUND:Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), enabling rapid tumour growth and immune evasion. Protein post-translational modification (PTM) crosstalk is a critical regulator of cellular processes; however, its contribution to metabolic reprogramming in HCC remains unclear. OBJECTIVE:To elucidate the function of the deubiquitinase JOSD1 in modulating PTM crosstalk and its impact on tumour glycolysis, progression and immunotherapy response in HCC. DESIGN:We combined multi-omics analyses with functional and mechanistic studies in cell lines, animal models and patient samples to characterise JOSD1 and its downstream pathways in HCC. RESULTS:JOSD1 was identified as a gene associated with glycolysis and correlated with a poor prognosis. Its over-expression promoted malignant phenotypes and enhanced glycolytic flux. Mechanistically, the JOSD1-AARS1 axis cooperatively regulates the ubiquitination-lactylation crosstalk at the K251 residue of PGAM1, thereby stabilising PGAM1, enhancing its enzymatic activity and promoting lactate accumulation. This metabolic shift impaired CD8+ T cell infiltration and function, promoting immune suppression. Therapeutically, liver-targeted inhibition of JOSD1 effectively suppressed tumour progression and synergised with anti-PD-1 therapy, leading to prolonged survival. CONCLUSION:The JOSD1-AARS1 axis regulates the ubiquitination-lactylation crosstalk on PGAM1, with JOSD1 acting as the critical upstream molecular switch that drives metabolic reprogramming and immune evasion in HCC. Targeting JOSD1 represents a promising therapeutic strategy to modulate tumour metabolism and improve immunotherapy efficacy.

Objective:To investigate the short-term efficacy and safety of Donafenib as postoperative adjuvant therapy for patients with high risk of recurrence after radical resection of hepatocellular carcinoma (HCC).Methods:The propensity score matching (PSM) and retrospective cohort study was conducted. The clinicopathological data of 157 HCC patients with high risk of recurrence after radical resection who were admitted to 6 medical centers, including The First Affiliated Hospital of Nanjing Medical University et al, from June 2021 to February 2023 were collected. There were 128 males and 29 females, aged (59±10)years. Of 157 patients, 101 cases undergoing Donafenib as postoperative adjuvant therapy were divided into the the Donafenib group, and 56 cases under-going no systemic postoperative adjuvant therapy were divided into the control group. Observation indicators: (1) PSM and comparison of general data of patients between the two groups after matching; (2) postoperative treatment; (3) follow-up and survival of patients; (4) analysis of risk factors affecting recurrence-free survival of patients. PSM was done based on the principle of optimal perfect matching, with the clamp value of 0.5, and the Donafenib group and the control group were matched at a ratio of 1.25∶1. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers and/or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data between groups was conducted using the Kruskal-Wallis H test. The Kaplan-Meier method was used to calculate survival rates and draw survival curves, and the Log-Rank test was used for survival analysis. The COX proportional hazard model was used for univariate and multivariate analyses. Results:(1) PSM and comparison of general data of patients between the two groups after matching. Of 157 patients, 126 cases were successfully matched, including 70 cases in the Donafenib group and 56 cases in the control group, respectively. The elimination of tumor number confounding bias ensured comparability between the two groups after PSM. (2) Postoperative treatment. After PSM, of 70 patients in the Donafenib group, there were 23 cases receiving Donafenib monotherapy, 26 cases combined with transcatheter arterial chemoembolization (TACE), 14 cases combined with immunotherapy, and 7 cases combined with TACE+immunotherapy. Of 56 patients in the control group, there were 37 cases receiving postoperative follow-up alone and 19 cases combined with TACE. (3) Follow-up and survival of patients. All 157 patients were followed up, and the follow-up time of the 101 patients in Donafenib group and the 56 patients in control group were 10.1(range, 6.3-14.6)months and 22.2(range, 15.1-25.5)months, respectively. During the follow-up period, 70 patients in the Donafenib group experienced treatment-related adverse reactions, inclu-ding 8 cases of grade 3 adverse reactions, 23 cases of grade 2 and 39 cases of grade 1 adverse reactions, respectively. After PSM, the postoperative 12-, 18-month recurrence-free survival rates were 83.7%, 83.7% in the 70 patients of Donafenib group and 67.8%, 58.9% in the 56 patients of control group, respectively, showing a significant difference in the postoperative recurrence-free survival time between the two groups ( hazard ratio=0.395, 95% confidence interval as 0.176-0.888, P<0.05). (4) Analysis of risk factors affecting recurrence free survival of patients. Results of multivariate ana-lysis showed that microvascular invasion, vascular thrombus, clinical stage as ⅢA were independent risk factors affecting recurrence-free survival in patients with high risk of recurrence after radical resection of HCC ( hazard ratio=2.181, 2.612, 2.612, 95% confidence interval as 1.028-4.629, 1.128-6.047, 1.128-6.047, P<0.05), Donafenib as postoperative adjuvant therapy was an independent protective factor affecting recurrence-free survival in patients with high risk of recurrence after radical resection of HCC ( hazard ratio=0.457, 95% confidence interval as 0.227-0.920, P<0.05). Results of further analysis showed that after PSM, there were significant differences in the postoperative recurrence-free survival time in patients with different clinical factors, including male, age ≥60 years, tumor diameter >5 cm, positive microvascular invasion, positive hepatitis B virus infection, alpha fetoprotein <200 μg/L, between the Donafenib group and the control group ( hazard ratio=0.283, 0.202, 0.174, 0.345, 0.273, 0.180, 95% confidence interval as 0.114-0.707, 0.044-0.937, 0.038-0.794, 0.128-0.929, 0.091-0.819, 0.052-0.620, P<0.05). Conclusion:Donafenib as postoperative adjuvant therapy can effectively reduce the short-term recurrence rate in patients with high risk of recurrence after radical resection of HCC, with good safety and tolerance.

BACKGROUND:Precise regulation of mitochondrial function is critical for liver regeneration. However, the underlying regulatory mechanism remains elusive. Here, we aimed to investigate the role of hepatocellular glutathione peroxidase 3 (GPX3) in liver regeneration. METHODS:In a 70% partial hepatectomy (PH) mouse model, immunostaining and single-cell RNA sequencing revealed significant enrichment but down-regulation of mitochondrial oxidative phosphorylation pathways post-PH, along with up-regulated hypoxia-inducible factor 1a (HIF-1a) and GPX3 in hepatocytes. Single-cell analysis confirmed peak GPX3 expression in hepatocytes at day 2 post-PH. Hepatocyte-specific GPX3 knockout impaired mitochondrial function and delayed liver regeneration. RESULTS:Mechanistically, immunoprecipitation-mass spectrometry and MitoCarta3.0 analysis identified voltage-dependent anion channel 1 (VDAC1) as a direct GPX3-binding partner. GPX3 interacted with VDAC1 via its A2 domain (residues 75-150), suppressing VDAC1 oligomerisation to restore mitochondrial Ca2+ homeostasis and preserve mitochondrial quality control (MQC). Notably, GPX3 deficiency promoted mitochondrial DNA (mtDNA) release, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Persistent STING hyperactivation increased interferon production while suppressing hepatocyte growth factor release, further inhibiting regeneration. Critically, GPX3 overexpression enhanced liver regeneration in both PH and hepatic ischemia-reperfusion injury models, underscoring its central role across regenerative stressors. CONCLUSIONS:In conclusion, GPX3 promotes liver regeneration by inhibiting VDAC1 oligomerisation to stabilise mitochondrial Ca2+ dynamics and MQC, while preventing mtDNA-mediated functional and phenotypic alterations in macrophages, positioning it as a therapeutic target for liver regeneration. KEY POINTS:GPX3 directly binds VDAC1 via its A2 domain to suppress VDAC1 oligomerisation, restoring mitochondrial Ca2 + homeostasis and preserving mitochondrial quality control during liver regeneration. GPX3 deficiency promotes mtDNA release, hyperactivating the cGAS-STING pathway in macrophages and suppressing hepatocyte growth factor (HGF) release. GPX3 overexpression enhances liver regeneration in both partial hepatectomy and hepatic ischemia-reperfusion injury models, highlighting its therapeutic potential.

Purpose:Hepatitis B virus infection is one of the most common risk factors leading to the development of intrahepatic cholangiocarcinoma (ICC). This study aims to determine the impact of antiviral treatment (AVT) on the survival outcomes of ICC patients with hepatitis B virus infection. Patients and Methods:This retrospective study included ICC patients who had HBV infection and underwent hepatectomy from May 2009 to June 2023 at a single medical center. Patients' baseline characteristics were analyzed, and the 14-year follow-up data were investigated using Kaplan-Meier curves and multivariable Cox proportional hazards regression models. The propensity score matching method was performed to balance the baseline differences between the AVT group and the non-AVT group. Results:A total of 229 patients were finally enrolled in the analysis. In the total cohort, 81 patients were classified into the AVT group and 148 patients into the non-AVT group. Kaplan-Meier curves showed that the AVT group exhibited prolonged overall survival and recurrence-free survival compared to the non-AVT group. Cox proportional hazards regression models revealed that AVT was an independent prognostic factor for both overall survival (HR 0.453, 95% CI: 0.280-0.732) and recurrence-free survival (HR 0.659, 95% CI: 0.436-0.997). A 1:1 nearest-neighbor matching algorithm was adopted, and 64 pairs of AVT and non-AVT patients were included in the propensity score matching cohort. Multivariable survival analyses confirmed AVT as a significant predictor for a favorable overall survival (HR 0.277, 95% CI: 0.147-0.519), but no statistical significance for recurrence-free survival was observed between the AVT group and the non-AVT group after propensity score matching. Conclusion:We analyzed the long-term follow-up data for ICC patients with hepatitis B virus infection who underwent hepatectomy. Notably, AVT exhibited a beneficial impact on overall survival for these postoperative ICC patients. However, our findings indicated no statistically significant effect of AVT on recurrence-free survival.

BACKGROUND & AIMS:Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC). Elucidating the molecules that influence fatty acid metabolism in HCC is important for developing precision therapies. However, uncovering the precise molecular mechanisms underlying changes in fatty acid metabolism in tumour cells is challenging. In this study, we aimed to determine the characteristics of fatty acid metabolism in HCC. METHODS:We employed organoid models, single-cell RNA sequencing, and spatial transcriptomics to identify key genes involved in tumour fatty acid metabolism. Metabolomics, proteomics, metabolic flux analysis, and transmission electron microscopy were utilized to evaluate this metabolic process. Tumour malignancy was characterized using multi-species models. Changes in the immune microenvironment were analysed by time-of-flight mass cytometry and multiplexed immunohistochemistry. Gene knockdown targeting the liver was achieved using lipid nanoparticles. RESULTS:Eukaryotic translation initiation factor 3 subunit f (eIF3f) is upregulated in HCC tissues and is associated with poor prognosis. eIF3f directly interacted with and stabilised long chain acyl CoA synthetase 4 (ACSL4) through K48-linked deubiquitination, promoting fatty acid biosynthesis and malignancy. The increased fatty acid levels in the tumour microenvironment indirectly reduced CD8+ T-cell infiltration. In addition, phosphorylated eIF3f enhanced the interaction between eIF3f and ACSL4. CONCLUSIONS:Targeting the eIF3f-ACSL4-fatty acid biosynthesis axis could decelerate the progression of HCC and enhance anti-programmed cell death-1 efficacy, implicating eIF3f as a potential target for precision therapy in HCC. IMPACT AND IMPLICATIONS:Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC), yet the underlying mechanisms involved remain unclear. Here, we found that eIF3f is upregulated in HCC and is associated with poor prognosis. eIF3f interacts with and stabilizes ACSL4, thereby promoting fatty acid biosynthesis. Additionally, increased fatty acid levels reduce CD8+ T-cell infiltration and activation. These findings are of significant importance for clinicians and researchers in the field of HCC treatment, as eIF3f inhibition combined with anti-PD-1 therapy significantly improved anti-tumour efficacy in a mouse model and could offer therapeutic benefits for patients. These findings have practical implications, as eIF3f could serve as a novel therapeutic target in HCC. However, further clinical studies are needed to confirm the efficacy of eIF3f targeting in human patients.

Fig. S7: Deletion of myeloid Trem2 reduces TGFβ in NASH

Background & Aims: Efferocytosis is essential for maintaining tissue homeostasis and resolving inflammation, but this process is compromised during sepsis. This study aimed to elucidate the role of neurite outgrowth inhibitor protein B (Nogo-B) in regulating macrophage efferocytosis under septic conditions and to evaluate its potential as a therapeutic target. Methods: We evaluated Nogo-B expression and efferocytosis in monocytes and monocyte-derived macrophages (MDMs) under septic conditions. Myeloid-specific Nogo deletion was used to assess its impact on MDM efferocytosis and septic organ injury. Mechanistic studies examined HIF-1α/ADAM17 signaling, mitochondrial calcium dynamics, metabolic activity, and endoplasmic reticulum (ER) stress. INCB081776, a dual MerTK/AXL inhibitor, was administered in vivo to suppress efferocytosis before mouse modeling. Statistical comparisons were performed using t tests or ANOVA. Results: Septic conditions upregulated Nogo-B expression and impaired efferocytosis in monocytes and MDMs, but not in peritoneal macrophages or Kupffer cells (n = 3–7, p <0.05). Myeloid Nogo deficiency significantly enhanced MDM efferocytosis and alleviated inflammatory liver and lung injury (n = 7, p <0.05). Mechanistically, Nogo-B disrupted ER–mitochondria calcium transfer, reduced mitochondrial calcium levels, and suppressed isocitrate dehydrogenase and succinate dehydrogenase activities. This led to impaired tricarboxylic acid (TCA) cycle function and oxidative phosphorylation (OXPHOS), resulting in succinate accumulation and an elevated succinate/α-ketoglutarate ratio. The metabolic shift activated HIF-1α/ADAM17 signaling, promoting MerTK/AXL cleavage and further impairing efferocytosis. Nogo deficiency also promoted MDM M2 polarization without affecting ER stress under lipopolysaccharide stimulation. Pharmacological inhibition of MerTK/AXL reversed the beneficial effects of myeloid Nogo deficiency on efferocytosis and septic liver and lung injury (n = 5, p <0.05). Conclusions: Nogo-B impairs MDM efferocytosis by suppressing OXPHOS and activating HIF-1α/ADAM17 signaling, thereby exacerbating septic liver and lung injury. Targeting Nogo-B offers a novel strategy to restore efferocytosis and alleviate sepsis. Impact and implications: Efferocytosis is compromised during sepsis, contributing to enhanced inflammation and organ damage. Our study identified Nogo-B as a critical mediator linking disrupted mitochondrial calcium uptake to impaired MDM efferocytosis. Targeting Nogo-B may represent a novel therapeutic strategy to restore efferocytosis and attenuate sepsis-related tissue injury. Further translational studies are needed to validate these findings in human disease.

Metabolic reprogramming is a hallmark of tumorigenesis and progression, with alterations in glucose metabolism, often referred to as the Warburg effect, playing a central role. This shift allows tumor cells to rapidly acquire energy and generate essential metabolic intermediates, thereby supporting enhanced growth. Despite its significance, the mechanisms by which tumor cells upregulate glycolysis remain inadequately understood. In this study, we report that YBX1 is highly expressed in hepatocellular carcinoma (HCC) and is closely associated with glycolysis. We show that YBX1 is modified by O-linked N-acetylglucosamine (O-GlcNAc) at threonine 57 (T57), which stabilizes the protein and increases its expression. This modification also promotes the phosphorylation of YBX1 at serine 102, facilitating its nuclear translocation. Consequently, this process enhances the transcription of glycolysis-related genes and stimulates lactate production. Moreover, YBX1 activates the transcription of P300, which in turn drives the lactylation of histones, particularly H3K18la. Cleavage Under Targets and Tagmentation (CUT&Tag) analysis reveals that H3K18 lactylation positively regulates YBX1 gene transcription. Our findings establish a positive feedback loop involving YBX1, glycolysis, and H3K18 lactylation that accelerates HCC progression. Disrupting this feedback loop may provide a novel therapeutic strategy for HCC.

Background: A significant portion of primary liver cancer patients in China are diagnosed at intermediate-to-advanced stages, often making them ineligible for curative surgery. Furthermore, high postoperative recurrence rates, reaching up to 70%, pose a major challenge for long-term survival. The emergence of novel systemic treatments, such as immune checkpoint inhibitor combinations, and advancements in locoregional therapies have created new opportunities for conversion and perioperative strategies. This updated consensus aims to standardize the clinical application of these therapies based on the latest evidence, with the objective of improving patient prognosis. Methods: A multidisciplinary committee of 97 experts was convened to revise previous guidelines. The process involved a comprehensive search of medical databases and conference proceedings, with evidence graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Consensus statements were finalized through a formal electronic voting process, requiring at least 80% agreement for approval, resulting in 18 updated statements. Results: The consensus provides refined definitions for conversion and perioperative therapy. It recommends various strategies for oncological conversion, including systemic therapy with anti-angiogenic drugs plus immunotherapy, and locoregional approaches like precision transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC). The document strongly affirms surgical resection as a crucial step for achieving long-term survival after successful conversion and offers guidance on surgical timing and adjuvant therapy. For resectable patients with high-risk features, neoadjuvant and adjuvant treatments are outlined to mitigate recurrence. The consensus also advocates for using dynamic enhanced magnetic resonance imaging ( MRI) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for efficacy assessment and underscores the essential role of a multidisciplinary team in management. Conclusions: This updated consensus offers standardized, evidence-based guidance for clinicians on implementing conversion and perioperative strategies to optimize patient-centered care and highlights the need for continued research to further refine these promising approaches.

e16279 Background: The high recurrence rate following resection presents a significant challenge to the survival of patients with resectable hepatocellular carcinoma (HCC). Therefore, it is imperative to develop novel and effective therapeutic interventions to reduce recurrence and improve the prognosis of patients with resectable HCC. This study aims to evaluate the efficacy and safety of camrelizumab combined with rivoceranib and TACE as a perioperative treatment regimen in patients with HCC. Methods: In this multicenter, randomized clinical trial, eligible HCC patients (CNLC stages Ib-IIIa) were randomly assigned in a 1:1 ratio to either the treatment or control group. Patients in the treatment group received one cycle of TACE, followed by 2 cycles of camrelizumab (200 mg Q2W) combined with rivoceranib (250 mg QD), and subsequently proceeded to surgery. At least six cycles of sequential therapy of camrelizumab (200 mg Q3W) plus rivoceranib (250 mg QD) was performed postoperatively.Patients in the control group received surgical resection followed by at least six cycles of treatment with camrelizumab (200 mg Q3W) plus rivoceranib (250 mg QD). The primary endpoint was 2-year event-free survival rate. Secondary endpoints were major pathological response (MPR) (defined as ≤10% viable tumor cells in the tumor bed), pathologic complete response rate (pCR), disease-free survival (DFS), overall survival (OS), and safety. Results: From March 2023 to November 2024, 60 patients with HCC were enrolled and randomly assigned to the treatment (31 patients) or control (29 patients) group. The median age of the enrolled subjects was 60 years (range: 31-76). Among them, 43 (71.7%) had hepatitis B virus (HBV) infection. In the treatment group, 28 patients received neoadjuvant therapy. Of these, 24 completed two cycles of preoperative therapy and underwent with the planned surgical resection. Surgery was canceled in 4 patients: 2 refused the procedure, and 2 had disease progression. The MPR rates in the ITT population were 22.6% (7/31). The MPR rate in patients who had surgical resection were 29.2% (7/24). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 5.9% of the treatment group and 10.2% of the control group. The most common TRAEs occuring in treatment group included platelet count decreased (22.5%), aspartate aminotransferase increased (19.3%) , and neutrophil count decreased (14.7%). Conclusions: The combination of camrelizumab, rivoceranib, and TACE as a perioperative treatment demonstrates both efficacy and tolerability in patients with resectable HCC. Preoperative neoadjuvant therapy has demonstrated promising pathological response. However, due to the short follow-up duration, further research is required to determine whether perioperative treatment can effectively reduce recurrence rates and improve long-term survival outcomes. Clinical trial information: NCT05613478 .

Supplementary Table. S1: Included control and NASH patients grouping and cohort information.

Background/Aims: Identifying patients with intrahepatic cholangiocarcinoma (ICC) likely to benefit from Methods: We analyzed bulk, single-cell and spatial transcriptomic data comprising 457 ICC patients to identify an immune-related score (IRS), followed by decoding its spatial immune context. We mapped radiomics profiles onto and multi-cohort validation covering 331 ICC patients. The signature was further explored for the potential therapeutic better survival and improved sensitivity to immunochemotherapy. We highlighted functional IRS-immune interactions cohort, and predicted treatment response with an area under the curve of up to 0.84 in immunochemotherapy cohort. remarkably curbed tumor growth, using in vitro ICC cell lines and in vivo humanized ICC patient-derived xenograft Conclusions: This proof-of-concept study sheds light on the spatially-resolved radiotranscriptomic signature to improve patient selection for emerging immunochemotherapy and high-order immunotherapy combinations in ICC.