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Background: This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. Methods: After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. Results: With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65–1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82–1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54–0.77). Conclusions: A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.

Abstract Background Positron Emission Tomography (PET) with combined [18F]-FDG and [11C]-acetate (dual-tracer) is used for the management of hepatocellular carcinoma (HCC) patients, although its prognostic value and underlying molecular mechanism remain poorly understood. We hypothesized that radiotracer uptake might be associated with tumor hypoxia and validated our findings in public and local human HCC cohorts. Methods Twelve orthotopic HCC xenografts were established using MHCC97L cells in female nude mice, with 5 having undergone hepatic artery ligation (HAL) to create tumor hypoxia in vivo. Tumors in both Control and HAL-treated xenografts were imaged with [11C]-acetate and [18F]-FDG PET-MR and RNA sequencing was performed on the resected tumors. Semiquantitative analysis of PET findings was then performed, and the findings were then validated on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and patients from our institution. Results HAL-treated mice showed lower [11C]-acetate (HAL-treated vs. Control, tumor-to-liver SUV ratio (SUVTLR): 2.14[2.05–2.21] vs 3.11[2.75–5.43], p = 0.02) but not [18F]-FDG (HAL-treated vs. Control, SUVTLR: 3.73[3.12–4.35] vs 3.86[3.7–5.29], p = 0.83) tumor uptakes. Gene expression analysis showed the PET phenotype is associated with upregulation of hallmark hypoxia signature. The prognostic value of the hypoxia gene signature was tested on the TCGA-LIHC cohort with upregulation of hypoxia gene signature associated with poorer overall survival (OS) in late-stage (stage III and IV) HCC patients (n = 66, OS 2.05 vs 1.67 years, p = 0.046). Using a local cohort of late-stage HCC patients who underwent dual-tracer PET-CT, tumors without [11C]-acetate uptake are associated with poorer prognosis (n = 51, OS 0.25 versus 1.21 years, p

Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment.

Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease’s progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions.

Background: Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function. Method: We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR. Result: Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor's aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier. Conclusion: G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes. [ABSTRACT FROM AUTHOR]

Background: Activated neutrophils release depolymerized chromatin and protein particles into the extracellular space, forming reticular Neutrophil Extracellular Traps (NETs). This process is accompanied by programmed inflammatory cell death of neutrophils, known as NETosis. Previous reports have demonstrated that NETosis plays a significant role in immune resistance and microenvironmental regulation in cancer. This study sought to characterize the function and molecular mechanism of NETosis-correlated long non-coding RNAs (NCLs) in the prognostic treatment of liver hepatocellular carcinoma (LIHC). Methods: We obtained the transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and evaluated the expression of NCLs in LIHC. A prognostic signature of NCLs was constructed using Cox and Last Absolute Shrinkage and Selection Operator (Lasso) regression, while the accuracy of model was validated by the ROC curves and nomogram, etc. In addition, we analyzed the associations between NCLs and oncogenic mutation, immune infiltration and evasion. Finally, LIHC patients were classified into four subgroups based on consensus cluster analysis, and drug sensitivity was predicted. Results: After screening, we established a risk model combining 5 hub-NCLs and demonstrated its reliability. Independence checks suggest that the model may serve as an independent predictor of LIHC prognosis. Enrichment analysis revealed a concentration of immune-related pathways in the high-risk group. Immune infiltration indicates that immunotherapy could be more effective in the low-risk group. Upon consistent cluster analysis, cluster subgroup 4 presented a better prognosis. Sensitivity tests showed the distinctions in therapeutic effectiveness among various drugs in different subgroups. Conclusion: Overall, we have developed a prognostic signature that can discriminate different LIHC subgroups through the 5 selected NCLs, with the objective of providing LIHC patients a more precise, personalized treatment regimen. [ABSTRACT FROM AUTHOR]

Simple Summary: TP is a widely utilized anticancer medication, particularly effective in treating HCC. Thorough investigation into TP's molecular mechanism in HCC treatment is crucial for precise and combination therapy. In this paper, we have unveiled a novel mechanism of TP in HCC treatment, where it inhibits tumor growth by reducing lipid accumulation. While the inhibition of P53 gene activity is commonly thought to be the reason for TP's effectiveness in treating HCC, this new mechanism serves as a significant complement to the current understanding, paving the way for innovative approaches to HCC treatment. Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease's progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC. [Display omitted] • Pyr regulates mitophagy by interfering with autophagosome-lysosome formation. • Pyr blocks autolysosomes formation by inhibiting SNAP29-VAMP8 interactions. • Pyr upregulates BNIP3 and induces the interaction of SNAP29 with BNIP3. • Restoration of the interaction between SNAP29 and VAMP8 by BNIP3 depletion. • Pyr enhances the sensitivity of HCC to Sora in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Treatment with immune checkpoint inhibitors (ICIs) is steadily becoming the standard of care for hepatocellular carcinoma (HCC), with an increasing number of immune-related adverse events (irAEs). However, only a small number of reports on the occurrence of diabetes mellitus (DM) in patients with HCC treated with ICIs have been published. In the present study, the clinical manifestations, laboratory findings, treatment and prognosis of three patients with advanced HCC were reported, who suffered immune-related DM when receiving treatment with ICIs. Furthermore, the relevant literature was reviewed in order to summarize clinical manifestations, possible mechanisms, diagnosis, prognosis of rechallenge and recommended management options, as well as clinical treatment suggestions. ICI-induced diabetes is rare but irAEs are potentially fatal, as diabetic ketoacidosis (DKA) is often the first manifestation. The incidence of immune-related DM is 0.86% and among those cases, the incidence of DKA is 59%. The combination of two ICIs markedly increases the risk. The human leukocyte antigen genotype, islet autoantibodies and autoreactive T cell-mediated β-cell destruction may be linked to the occurrence of immune-related DM. Patient education and clinicians' awareness of ICI-related DM are good management options. Adequate clinical judgment, close monitoring and early detection are also needed to decide whether to continue immunotherapy or to rechallenge it, so as to achieve the maximum benefit of clinical treatment. [ABSTRACT FROM AUTHOR]

Timely liver function recovery (LFR) is crucial for postoperative hepatocellular carcinoma (HCC) patients. Here, we established the significance of LFR on patient long-term survival through retrospective and prospective cohorts and identified a key gut microbe, Bifidobacterium longum , depleted in patients with delayed recovery. Fecal microbiota transfer from HCC patients with delayed recovery to mice similarly impacted recovery time post hepatectomy. However, oral gavage of B. longum improved liver function and repair in these mice. In a clinical trial of HCC patients, orally administering a probiotic bacteria cocktail containing B. longum reduced the rates of delayed recovery, shortened hospital stays, and improved overall 1-year survival. These benefits, attributed to diminished liver inflammation, reduced liver fibrosis, and hepatocyte proliferation, were associated with changes in key metabolic pathways, including 5-hydroxytryptamine, secondary bile acids, and short-chain fatty acids. Our findings propose that gut microbiota modulation can enhance LFR, thereby improving postoperative outcomes for HCC patients. [Display omitted] • Postoperative liver function recovery is a key prognostic factor for HCC patients • Normal liver function recovery in HCC patients is associated with fecal B. longum • Administering B. longum to HCC patients promotes postoperative liver function recovery • B. longum improves liver function by modulating gut microbiota and metabolites Yu et al. report that Bifidobacterium longum can mitigate liver inflammation and fibrosis by modulating the gut microbiota and metabolites. Orally administering B. longum to HCC patients during the perioperative period promotes postoperative liver function recovery, boosts 1-year survival, and shortens hospital stays, offering a promising intervention for HCC patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components that significantly contribute to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remain unclear. We screened and validated diacylglycerol kinase gamma (DGKG) hyper-expression specifically in HCC tumor vascular ECs. Single-cell RNA-sequencing, cytometry by time-of-flight, and in vitro and in vivo studies were performed to investigate the functions of endothelial DGKG. Multiplexed immunohistochemistry staining and flow cytometry were used to evaluate changes in the TME. Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T-cell differentiation in HCC. Of significance, we found that HIF-1α activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 to facilitate ZEB2 deubiquitination, which increases TGF-β1 secretion, thus inducing tumor angiogenesis and regulatory T-cell differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2. Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-β1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC. Here, we reported that hypoxia-induced endothelial cell-specific DGKG hyper-expression promotes angiogenesis and immune evasion in HCC by recruiting USP16 for K48-linked deubiquitination and inducing the subsequent stabilization of ZEB2, leading to increased TGF-β1 secretion. Most importantly, endothelial DGKG inhibition greatly improved the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, significantly inhibiting the malignant progression of HCC and improving survival. This preclinical study supports the targeting of endothelial DGKG as a potential strategy for precision HCC treatment. [Display omitted] • DGKG is hyper-expressed in HCC tumor vascular ECs and predicts poor survival. • Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immunosuppression. • DGKG recruits USP16 to facilitate ZEB2 deubiquitination, thus activating the TGF-β1 positive feedback loop. • Targeting endothelial DGKG enhances the efficacy of dual PD-1 and VEGFR-2 blockade. [ABSTRACT FROM AUTHOR]

'Xiayuxue decoction' (XYXD) is a traditional Chinese medicine compound, composing of three natural medicines: Rheum officinale Baill., Prunus persica (L.) Batsch and Eupolyphaga sinensis Walker. It is derived from the famous traditional Chinese medical classics 'Jingui Yaolue' and has been used for thousands of years. In the Guidelines for the Diagnosis and Treatment of Primary liver Cancer issued by China's Health Commission, XYXD was applied in the treatment of primary liver cancer. To clarify the pharmacodynamic material basis and mechanism of XYXD in the treatment of hepatocellular carcinoma (HCC). Firstly, the active components of XYXD and its distribution in vivo were identified by Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Then, the effective components and mechanism of XYXD against HCC were explored by network pharmacology combined with cell experiments in vitr o. Furthermore, the anti-HCC effect of XYXD was determined by animal experiments in vivo. Metagenomic sequencing was used to detect its effect in gut microbiota, and targeted metabolism was used to detect the changes of bile acids in the liver. Finally, the related targets of NKT cell immune function activation were detected by RT-qPCR and Elisa. A total of 113 active ingredients in XYXD were identified, and the distribution of active ingredients in blood, liver, tumor, cecum, intestinal contents and feces was clarified. The circulation process and active ingredient group of XYXD were preliminarily clarified. In addition, we found five anti-HCC active ingredients in XYXD through network pharmacology combined with cell experiments in vitro, among which aloe emodin had the most significant effect, and predicted the potential mechanism of XYXD against HCC through NKT cell pathway. Moreover, the inhibitory effect of XYXD on liver tumor growth was clarified by animal experiments in vivo. The mechanism was mainly to promote the production of bile salt hydrolase (BSH) by increasing the abundance of Bacteroides and Lactobacillus , BSH converts conjugated bile acids into primary bile acids, and reduces the conversion of primary bile acids to secondary bile acids by reducing the abundance of Eubacterium , thereby increasing the content of primary bile acids. Primary bile acids trigger NKT cells in the liver to produce interferon-γ to exert anti-HCC immune effects. This study found that the traditional Chinese herbal formula XYXD can trigger the immune effect of NKT cells against HCC by regulating the interaction between gut microbiota and bile acids. [Display omitted] • Study completely analyzed pharmacodynamic material basis of XYXD. • Study identified potential anti-hepatocellular carcinoma compounds of XYXD. • XYXD promotes production of primary bile acids by regulating gut microbiota. • XYXD triggers NKT cells immune function against-HCC through primary bile acids. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment. [Display omitted] • Alterations of enzymes in HCC metabolic reprogramming networks have important implications for therapeutic resistance. • Targeting enzymes in HCC metabolic reprogramming networks could eliminate therapeutic resistance. • Crosstalk between pathways exists in HCC metabolic reprogramming networks. • The exploration of HCC metabolic reprogramming networks relies on comprehensive detection assays. • Drug delivery systems help eliminate therapeutic resistance by interfering with metabolic reprogramming networks. [ABSTRACT FROM AUTHOR]