Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study.

Background: The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. Methods: We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. Results: Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. Conclusions: Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Strategies to enhance the response of liver cancer to pharmacological treatments.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

Correction: Méndez-Blanco et al. Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells. Cancers 2019, 11, 1984.

In the original publication [...].

Impact of Aberrant ß-Catenin Pathway on Cholangiocarcinoma Heterogeneity.

The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/ß-catenin pathway plays a pivotal role. Alteration of ß-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/ß-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease.

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.

Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation.

Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.

Anti-retinal Antibodies in Sarcoidosis.

PURPOSE: To measure, characterize, and evaluate the clinical significance of anti-retinal antibodies in patients with sarcoid uveitis. SUBJECTS/METHODS: Prospective study of anti-retinal antibodies in 45 patients with biopsy-proven sarcoidosis (25 with and 20 without uveitis). Results were compared with patients with confirmed infectious uveitis (n = 40) and non-infectious uveitis (n = 40). RESULTS: Among sarcoidosis patients, anti-retinal antibodies were positive in 23/25 patients with uveitis and in 15/20 without uveitis [P = ns]. The most common antigens recognized were carbonic anhydrase II (14/23) and α-enolase (6/23). Anti-carbonic anhydrase II autoantibodies were infrequently detected in sarcoidosis patients without uveitis (2 out 15, P < .001), in patients with infectious uveitis (1 out 18, P < .001), and in patients with non-infectious uveitis (8 out 37, P < .001). CONCLUSIONS: Anti-retinal antibodies recognizing carbonic anhydrase II are common in sarcoid uveitis. Although not fully sensitive and specific, they might be a useful non-invasive diagnostic tool for the diagnosis of sarcoid uveitis.

Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies.

Neuropilin-1 (NRP1) is a transmembrane protein involved in numerous cellular functions which has had increasing interest from cancer researchers. Liver cancer and colorectal cancer (CRC) are two of the most frequent and deadly tumors with a complex pharmacological framework. Here, we assessed the prognostic, diagnostic and clinicopathological value of NRP1 in liver cancer and CRC patients. We searched PubMed, Scopus, Web of Science, Embase and Cochrane Library databases for articles evaluating the NRP1 correlation with survival parameters, tumor development or clinicopathological features. Hazard ratios and odds ratios with 95% confidence intervals were extracted or estimated by Parmar method and pooled to evaluate the overall effect size with STATA 16 software. Heterogeneity was analyzed by chi-square-based Q test and I2 statistic, along with meta-regression and subgroup analysis, and publication bias was assessed by funnel plot asymmetry and Egger's test. The study protocol was registered in PROSPERO (CRD42022307062). NRP1 overexpression was significantly correlated with lower survival in liver cancer patients and with tumor development in hepatocarcinoma patients, and was strongly correlated with an increased risk of vascular invasion in liver cancer and metastasis in CRC and liver tumors. These results support the role of NRP1 as a potential and useful biomarker in both types of cancer.

Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers.

Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence.

Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N-acetyl-5-methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti-inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti-inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.

Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib.

Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.

Association of FOXO3 Expression with Tumor Pathogenesis, Prognosis and Clinicopathological Features in Hepatocellular Carcinoma: A Systematic Review with Meta-Analysis.

Forkhead box O3 (FOXO3), an essential transcription factor related to liver disease, has been linked to cancer progression. The most frequent primary liver tumor, hepatocellular carcinoma (HCC), has an elevated mortality rate and patient outcomes remain very poor. Here, we examined the diagnostic, prognostic and clinicopathological significance of FOXO3 expression in HCC. We systematically searched Cochrane, Embase, PubMed, Scopus and Web of Science. Articles analyzing FOXO3 levels in HCC patient samples and its relationship with tumor development, survival or clinicopathological factors were selected. Hazard ratios, odds ratios and 95% confidence intervals were extracted, estimated by Parmar method or calculated and pooled across studies. Heterogeneity was evaluated by chi-square-based Q and I2 tests, while publication bias by funnel plots and Egger's test. Subgroup analysis was performed when heterogeneity was evident. The study protocol was registered in PROSPERO (CRD42021237321), and data were meta-analyzed employing STATA 16. Five studies involving 1059 HCC cases were finally included in this meta-analysis, finding that high FOXO3 levels significantly correlate with HCC development and shorter overall survival. Moreover, subgroup analysis revealed a significant association between positive FOXO3 expression and the risk of invasion. Thus, FOXO3 could function as a novel biomarker with diagnostic and prognostic value in HCC.

Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics.

Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.

Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. METHODS: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I 2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger's test. RESULTS: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor-node-metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. CONCLUSIONS: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells.

Despite sorafenib effectiveness against advanced hepatocarcinoma (HCC), long-term exposure to antiangiogenic drugs leads to hypoxic microenvironment, a key contributor to chemoresistance acquisition. We aimed to study the role of hypoxia in the development of sorafenib resistance in a human HCC in vitro model employing the HCC line HepG2 and two variants with acquired sorafenib resistance, HepG2S1 and HepG2S3, and CoCl2 as hypoximimetic. Resistant cells exhibited a faster proliferative rate and hypoxia adaptive mechanisms, linked to the increased protein levels and nuclear translocation of hypoxia-inducible factors (HIFs). HIF-1α and HIF-2α overexpression was detected even under normoxia through a deregulation of its degradation mechanisms. Proapoptotic markers expression and subG1 population decreased significantly in HepG2S1 and HepG2S3, suggesting evasion of sorafenib-mediated cell death. HIF-1α and HIF-2α knockdown diminished resistant cells viability, relating HIFs overexpression with its prosurvival ability. Additionally, epigenetic silencing of Bcl-2 interacting protein 3 (BNIP3) was observed in sorafenib resistant cells under hypoxia. Demethylation of BNIP3 promoter, but not histone acetylation, restored BNIP3 expression, driving resistant cells' death. Altogether, our results highlight the involvement of HIFs overexpression and BNIP3 methylation-dependent knockdown in the development of sorafenib resistance in HCC. Targeting both prosurvival mechanisms could overcome chemoresistance and improve future therapeutic approaches.

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review.

Quercetin is a flavonoid present in fruits, vegetables and plants with antioxidant, anti-inflammatory and anticancer properties. Its beneficial activities have been demonstrated in different human pathologies, including hepatoprotective effects against liver disorders. High mortality and late diagnosis of the primary liver tumor hepatocarcinoma (HCC) makes this cancer an interesting target for the study of quercetin effects. Our aim was to systematically review antitumor activities of quercetin in HCC preclinical studies employing single, encapsulated, combined or derived quercetin forms. Literature search was conducted in PubMed, Scopus and Web of Science (WOS), and 39 studies were finally included. We found that 17 articles evaluated quercetin effects alone, six used encapsulated strategy, 10 combined this flavonoid, two decided to co-encapsulate it and only four studied effects of quercetin derivatives, highlighting that only nine included in vivo models. Results evidence the quercetin antiproliferative and proapoptotic properties against HCC either alone and with the mentioned strategies; nevertheless, few investigations assessed specific activities on different processes related with cancer progression. Overall, further studies including animal models are needed to deeper investigate the precise mechanisms of action of quercetin as antitumor agent, as well as the potential of novel strategies aimed to improve quercetin effects in HCC.