Strategy For Treatment Of Hepatocellular Carcinoma Research Articles

Revamping Hepatocellular Carcinoma Immunotherapy: The Advent of Microbial Neoantigen Vaccines.

Immunotherapy has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC). However, its efficacy varies significantly with each patient's genetic composition and the complex interactions with their microbiome, both of which are pivotal in shaping anti-tumor immunity. The emergence of microbial neoantigens, a novel class of tumor vaccines, heralds a transformative shift in HCC therapy. This review explores the untapped potential of microbial neoantigens as innovative tumor vaccines, poised to redefine current HCC treatment modalities. For instance, neoantigens derived from the microbiome have demonstrated the capacity to enhance anti-tumor immunity in colorectal cancer, suggesting similar applications in HCC. By harnessing these unique neoantigens, we propose a framework for a personalized immunotherapeutic response, aiming to deliver a more precise and potent treatment strategy for HCC. Leveraging these neoantigens could significantly advance personalized medicine, potentially revolutionizing patient outcomes in HCC therapy.

Combination Therapy Consisting of Transarterial Chemoembolization, Lenvatinib, and Programmed Cell Death Protein 1 Blockade for Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus: A Case Series Study and Literature Review

Introduction: Patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) have poor prognosis. Combination therapy involving the blockade of programmed cell death protein 1 (PD-1) and tyrosine kinase inhibitors is an efficient treatment strategy for advanced HCC. However, surgical treatment after a combination of systemic therapy and transarterial chemoembolization (TACE) for HCC with IVCTT has not been widely reported, and the efficacy and safety of this treatment have not been studied. Methods: In the 21 cases reported herein, the patients were treated with TACE, lenvatinib, and PD-1 blockade. The treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated, and the related literature was reviewed. Results: The overall response and disease control rates were 66.7% and 85.7%, respectively. The median PFS time was 16.0 months, with a 1-year PFS rate of 55.60%. The median OS was not reached, with a 1-year OS rate of 66.70%. Four patients underwent hepatectomy without serious complications and survived for 29.1, 24.7, 14.2, and 13.8 months. Three patients survived tumor-free, and 1 patient experienced intrahepatic recurrence. Pathological complete response and major pathological responses were observed in 1 and 3 patients, respectively. Treatment-related adverse events of any grade occurred in 8/9 patients (88.9%), and grade 3 treatment-related adverse events occurred in 1 patient. Conclusion: The combination of TACE, lenvatinib, and PD-1 is effective for HCC with IVCTT and has acceptable adverse effects.

Microspheres-mediated magnetic thermal ablation combined with immune checkpoint blockade therapy for liver cancer

Hepatocellular carcinoma (HCC) are some of the most difficult malignant tumors to treat, due to their high rates of metastasis and recurrence. Image-guided percutaneous ablation, which serves as an important means in HCC treatment. However, drawbacks such as puncture injury, metastasis, and a limited ablation range still exist. Therefore, A highly effective and non-invasive magnetic thermal ablation (MTA) scheme for HCC was proposed by precisely embolizing magnetic microspheres into tumor-feeding arteries. In this study, polyacrylamide (PAM) and ferric oxide (Fe3O4) were utilized to prepare uniformly sized PAM@Fe3O4 microspheres with excellent eddy current heating effects. Additionally, a combined approach of MTA and immunotherapy was suggested. MTA combined with immune checkpoint blockade therapy efficiently ablated primary tumors and inhibited simulated metastatic tumors in mice. Further arterial embolization experiments in rabbit ears and renal arteries demonstrated the effective retention of PAM@Fe3O4 microspheres in blood vessels for MTA. Finally, we successfully applied PAM@Fe3O4 microspheres for efficient MTA therapy in a rabbit VX2 in situ liver tumor model. The aim of research is to provide new strategies for clinical HCC treatment, promoting the transition from image-guided percutaneous minimally invasive ablation to noninvasive ablation. This significant transition holds the potential for clinical applicability.

Cucurbitacin I exerts its anticancer effects by inducing cell cycle arrest via the KAT2a-ube2C/E2F1 pathway and inhibiting HepG2-induced macrophage M2 polarization

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, particularly prevalent in China, where it accounts for nearly half of the world's new cases and deaths each year, but has limited therapeutic options. This study systematically investigated the impact of cucurbitacin I on HCC cell lines including SK-Hep-1, Huh-7, and HepG2. The results revealed that cucurbitacin I not only inhibited cell proliferation, cell migration and colony formation, but also induced apoptosis in HCC cells. The apoptotic induction was accompanied by a decrease in the expression of the anti-apoptotic factor B-cell lymphoma 2 (Bcl2), and an elevation in the expression levels of pro-apoptotic factors, including tumor protein p53 (P53), bcl2 associated X-apoptosis regulator (Bax), and caspase3 (Cas3). Additionally, cucurbitacin I caused cell cycle arrest by modulating the lysine acetyltransferase 2A (KAT2A)-E2F transcription factor 1 (E2F1)/Ubiquitin-conjugating enzyme E2 C (UBE2C) signaling axis. In terms of regulation on tumor microenvironment, cucurbitacin I was demonstrated the ability to inhibit HCC cell-induced M2 polarization of macrophages. This comprehensive study unveils the multifaceted anti-cancer mechanisms of cucurbitacin I, providing robust support for its potential application in the treatment of HCC, offering new avenues for the future development of HCC treatment strategies.

Biohybrid hydrogel inhibiting β-klotho/HDAC3 axis for hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.

Lefamulin Overcomes Acquired Drug Resistance via Regulating Mitochondrial Homeostasis by Targeting ILF3 in Hepatocellular Carcinoma.

Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)-approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line-derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer-binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine-99 site of ILF3 protein and interferes with acetyltransferase general control non-depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine-100 site, which disrupts the ILF3-mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib.

Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.

HRAS Induces Ferroptosis through Upregulating HSPB1 in Hepatocellular Carcinoma.

The aim of this study is to explore the mechanism of HRAS and HSPB1 in ferroptosis. Primary liver cancer is the third leading cause of tumor death worldwide. Hepatocellular carcinoma (HCC) constitutes 75%-85% of cases of primary liver cancer. HRAS and HSPB1 co-express in multiple cells and participate in tumor progression regulation. However, their expression regulation and role in HCC have not been reported. We investigated the effects of HRAS and HSPB1 on ferroptosis in in vitro experiments. Here, the role and mechanism of HRAS and HSPB1 on ferroptosis were investigated by transfecting the specific siRNA or overexpressing plasmids in HCC cells. Bioinformatics analysis proved that HRAS and HSPB1 were highly expressed in HCC tissues and associated with poor prognosis of patients with HCC. In vitro, HRAS overexpression reduced the level of intracellular iron, ROS, and MDA production in HCC cells. Mechanistically, HRAS increased GPX4 expression and decreased the levels of ACSL4 and P53. HRAS also increased HSPB1 expression, and HRAS knockdown downregulated HSPB1 levels in HCC cells. Importantly, overexpression of HSPB1 reversed HRAS-increased concentration of iron, MDA, and ROS and eliminated HRAS-induced ferroptosis. Moreover, HRAS enhanced the proliferation and invasion by targeting HSPB1. The regulation of HSPB1 by HRAS enhanced the resistance of HCC cells to ferroptosis. HRAS promoted proliferation and invasion by upregulating HSPB1. This research provides a new potential strategy for HCC treatment.

Hepatocellular Carcinoma in Asia: Physician and Patient Perspectives on Surveillance, Diagnosis, and Treatment

PurposeIn several Asian countries, hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. HCC risk factors in Asia differ from those elsewhere and are changing with the treatment landscape as systemic treatment options increase. This study was conducted to gain insight from physicians and patients into HCC screening, diagnosis, and treatment strategies in Indonesia, Korea, Malaysia, Singapore, Taiwan, Thailand, and Vietnam.MethodsTwo cross-sectional, anonymized, online surveys were completed between July and December 2022 by physicians diagnosing and treating HCC (55 questions on risk factors, surveillance, diagnosis, and treatment) and patients ≥ 18 years old diagnosed with HCC (36 questions on disease knowledge, quality of life, and experiences of diagnosis and treatment).ResultsResponses were received from 276 physicians in all 7 countries and 130 patients in Thailand, Taiwan, and Vietnam. From the physician’s perspective, surveillance programs are widespread but identify insufficient HCC cases; only 18% are early-stage HCC at diagnosis. From the patient’s perspective, knowledge of risk factors increases after diagnosis, but few seek support from patient associations; patients would benefit from better communication from their doctors. Treatment affordability and side effects are key issues for patients.ConclusionsAwareness of the risk factors for HCC should be raised in primary care and the general population, and surveillance should identify early-stage HCC. Because patients rely on their doctors for support, doctors should better understand their patients’ needs, and patients could be supported by trained nurses or case managers. Programs are needed to increase patients’ access to proven HCC treatments.

Racial/Ethnic Disparities and Immunotherapeutic Advances in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains one of the leading causes of death among many associated liver diseases. Various conventional strategies have been utilized for treatment, ranging from invasive surgeries and liver transplants to radiation therapy, but fail due to advanced disease progression, late screening/staging, and the various etiologies of HCC. This is especially evident within racially distinct populations, where incidence rates are higher and treatment outcomes are worse for racial/ethnic minorities than their Caucasian counterparts. However, with the rapid development of genetic engineering and molecular and synthetic biology, many novel strategies have presented promising results and have provided potential treatment options. In this review, we summarize past treatments, how they have shaped current treatments, and potential treatment strategies for HCC that may prove more effective in the future.

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs’ half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. Statement of significanceTreatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Research progress in the metabolic reprogramming of hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and its morbidity is increasing worldwide due to increasing prevalence. Metabolic reprogramming has been recognized as a hallmark of cancer and serves a role in cancer progression. Glucose, lipids and amino acids are three major components whose altered metabolism can directly affect the energy production of cells, including liver cancer cells. Nutrients and energy are indispensable for the growth and proliferation of cancer cells, thus altering the metabolism of hepatoma cells can inhibit the progression of HCC. The present review summarizes recent studies on tumour regulatory molecules, including numerous noncoding RNAs, oncogenes and tumour suppressors, which regulate the metabolic activities of glucose, lipids and amino acids by targeting key enzymes, signalling pathways or interactions between the two. These regulatory molecules can regulate the rapid proliferation of cancer cells, tumour progression and treatment resistance. It is thought that these tumour regulatory factors may serve as therapeutic targets or valuable biomarkers for HCC, with the potential to mitigate HCC drug resistance. Furthermore, the advantages and disadvantages of metabolic inhibitors as a treatment approach for HCC, as well as possible solutions are discussed, providing insights for developing more effective treatment strategies for HCC.

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review).

Hepatocellular carcinoma (HCC), one of the leading causes of cancer‑related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi‑tyrosine kinase inhibitors approved for first‑line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non‑apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

CRISPR/Cas9 screen reveals that targeting TRIM34 enhances ferroptosis sensitivity and augments immunotherapy efficacy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by complex heterogeneity and drug resistance. Resistance to ferroptosis is closely related to the progression of HCC. While HCC tumors vary in their sensitivity to ferroptosis, the precise factors underlying this heterogeneity remain unclear. In this study, we sought to elucidate the mechanisms that contribute to ferroptosis resistance in HCC. Whole-genome CRISPR/Cas9 screen using a subtoxic concentration (IC20) of ferroptosis inducer erastin in the HCC cell line Huh7 revealed TRIM34 as a critical driver of ferroptosis resistance in HCC. Further investigation revealed that TRIM34 suppresses ferroptosis in HCC cells, promoting their proliferation, migration, and invasion both in vitro and in vivo. Furthermore, TRIM34 expression is elevated in HCC tumor tissues, correlating with a poor prognosis. Mechanistically, TRIM34 directly interacts with Up-frameshift 1 (UPF1), a core component of the nonsense-mediated mRNA decay (NMD) pathway, to promote its ubiquitination and degradation. This interaction suppresses GPX4 transcript degradation, thus promoting the protein levels of this critical ferroptosis suppressor in HCC. In light of the close crosstalk between ferroptosis and the adaptive immune response in cancer, HCC cells with targeting knockdown of TRIM34 exhibited an improved response to anti-PD-1 treatment. Taken together, the TRIM34/UPF1/GPX4 axis mediates ferroptosis resistance in HCC, thereby promoting malignant phenotypes. Targeting TRIM34 may thus represent a promising new strategy for HCC treatment.

Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis

Background Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown.MethodsCell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels.Results Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels.Conclusions These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

Integrated Single Cell Analysis Reveals An Atlas of Tumor Associated Macrophages in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), one of the most prevalent cancers globally, is closely associated with tumor-associated macrophages (TAMs), including monocyte-derived macrophages and liver-resident Kupffer cells. Understanding TAM heterogeneity at the cellular level is crucial for developing effective HCC prevention and treatment strategies. In this study, we conducted an integrated single-cell analysis of four cohorts (GSE140228, GSE125449, GSE149614 and GSE156625) to elucidate the TAM landscape in HCC. We identified 284 gene markers, termed Panmyeloid markers, that characterize myeloid cells within this context. Our analysis distinguished six clusters of monocyte-derived macrophages (Macro1-Macro6) and four clusters of Kupffer cells (Kupffer1-Kupffer4). Notably, CXCL10 + macrophages and MT1G + Kupffer cells, predominantly located within tumor tissues, exhibited distinct functional characteristics relevant to HCC. We also explored cellular communication between TAMs and T cells, uncovering potential signaling pathways such as the CXCL10/CXCL11-CXCR3 and CXCL12-CXCR4 networks. These findings enhance our understanding of TAMs in HCC and open new avenues for targeted therapeutic interventions.

Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase (G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis.

Betaine-homocysteine methyltransferase (BHMT) regulates protein methylation and is correlated with tumorigenesis; however, the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored. Here, we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma (HCC) using tissue samples from 198 patients. BHMT was to be frequently found (86.6%) expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC. Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo, whereas complete knockout of Bhmt (Bhmt-/-) produced the opposite effect. We combined proteomics, metabolomics, and molecular biological strategies and detected that Bhmt-/- promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models. In contrast, restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis. Additionally, coimmunoprecipitation identified monomethylated modifications of the G6PD, and BHMT regulated the methylation of G6PD. Protein sequence analysis, generation and application of specific antibodies, and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246. Furthermore, we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD, thereby inhibiting G6PD activity, which in turn suppressed hepatocarcinogenesis. Taken together, this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency, suggesting a potential therapeutic strategy for HCC treatment.

Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway.

Management of hepatocellular carcinoma (HCC) remains challenging due to population growth, frequent recurrence and drug resistance. Targeting of genes involved with the ferroptosis is a promising alternative treatment strategy for HCC. The present study aimed to investigate the effect of dihydroartemisinin (DHA) against HCC and explore the underlying mechanisms. The effects of DHA on induction of ferroptosis were investigated with the measurement of malondialdehyde concentrations, oxidised C11 BODIPY 581/591 staining, as well as subcutaneous xenograft experiments. Activated transcription factor 4 (ATF4) and solute carrier family 7 member 11 (SLC7A11 or xCT) were overexpressed with lentiviruses to verify the target of DHA. Here, we confirmed the anticancer effect of DHA in inducing ferroptosis is related to ATF4. High expression of ATF4 is related to worse clinicopathological prognosis of HCC. Mechanistically, DHA inhibited the expression of ATF4, thereby promoting lipid peroxidation and ferroptosis of HCC cells. Overexpression of ATF4 rescued DHA-induced ferroptosis. Moreover, ATF4 could directly bound to the SLC7A11 promoter and increase its transcription. In addition, DHA enhances the chemosensitivity of sorafenib on HCC invivo and invitro. These findings confirm that DHA induces ferroptosis of HCC via inhibiting ATF4-xCT pathway, thereby providing new drug options for the treatment of HCC.

IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis.

Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.