非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展北大核心

非酒精性脂肪性肝病(NAFLD)正逐渐成为肝细胞癌(HCC)的主要病因。到2030年,NAFLD相关肝癌的年发病率预计将增加45%~130%。尽管NAFLD已成为严重的全球健康威胁,但NAFLD相关HCC的分子机制仍不清楚,需要进一步探索,而NAFLD在HCC中的作用应该引起足够的关注。本文综述了NAFLD相关HCC流行病学最新进展,阐述了遗传易感性、肠道微生物群、代谢紊乱和免疫机制在促进NAFLD进展为HCC进程中的作用机制最新进展,为认识NAFLD相关HCC的现状和发病机制奠定基础。     

Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease

Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD-HCC has been recognized to have clinico-histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD-HCC occurs in the absence of cirrhosis, the imbalance of pro- and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC-prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD-affected livers, such as a fatty-acid-induced loss of cytotoxic CD4 T cells serving for immune surveillance and “auto-aggressive” CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH-HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory–Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid-rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an “oncometabolite.” Genome-wide analyses suggested that SH-HCC may be more responsive to ICIs given its mutual exclusiveness with β-catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD-specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.     

非酒精性脂肪肝对免疫检查点抑制剂治疗肝细胞癌疗效的影响及机制研究进展

近年来,非酒精性脂肪肝合并肝细胞癌的患者数量逐渐上升,免疫治疗在晚期肝细胞癌的治疗中扮演着越来越重要的角色。既往研究发现非酒精性脂肪肝可以影响肝细胞癌免疫治疗的疗效,但机制不清,可能与这些因素相关：非酒精性脂肪肝中CD8⁺PD-1⁺T细胞增多导致肝脏细胞增殖能力缺陷;锌指蛋白64激活CSF1抑制抗肿瘤免疫;PCSK9下调LDLR水平抑制肿瘤微环境中CD8⁺T细胞免疫应答;免疫应答的缺失导致肝损伤等。研究发现联合使用仑伐替尼、PKCa抑制剂、PCSK9蛋白的抑制、铁死亡诱导剂、HIF2a小分子抑制剂可以改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂的疗效。本文就非酒精性脂肪肝对肝脏免疫微环境和肝细胞癌免疫检查点抑制剂疗效的影响和机制,以及如何改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂疗效的研究进行综述。     

Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.     

T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy

Hepatocellular carcinoma (HCC) is characterized by poor outcome and shows limited drug-response in clinical trials. Tumor immune microenvironment (TIME) exerts a strong selection pressure on HCC, leading to HCC evolvement and recurrence after multiple therapies. T cell-mediated immunoreaction during cancer surveillance and clearance is central in cancer immunity. Heterogenous T cell subsets play multiple roles in HCC development and progression. The re-educated T cells in TIME usually lead to deteriorated T cell response and tumor progression. Investigation into immune system dysregulation during HCC development will shed light on how to turn immune suppressive state to immune activation and induce more efficient immune response. Emerging T cell-based treatment such as cancer vaccines, CAR-T cell therapy, adoptive cell therapy, and immune checkpoint inhibitors (ICIs), have been proved to cause tumor regression in some clinical and preclinical trials. In this review, we focused on recent studies that explored T cells involved in HCC and how they affect the course of disease. We also briefly outlined current T cell-based immunotherapies in HCC.     

TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease‐related hepatocellular carcinoma

The number of patients with nonalcoholic fatty liver disease (NAFLD)‐related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD‐related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD‐HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD‐HCC tumor samples from these 10 patients by whole‐exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole‐exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD‐HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole‐exome sequencing and 14 representative HCC‐associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array‐based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD‐HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD‐HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD‐related liver carcinogenesis.     

Clinical,Epidemiological and Histopathological Aspects in Patients with Hepatocellular Carcinoma Undergoing Liver Transplantation

Background: Hepatocellular Carcinoma (HCC) is the primary liver cancer with high incidence and mortality rates.Currently one of the major etiologies for liver disease, HCC and liver transplantation is nonalcoholic fatty liver disease(NAFLD). The aim of the present study was to evaluate the epidemiological, histopathological and clinical aspects ofHCC transplant patients, with emphasis on NAFLD etiology. Methods: This study included all HCC patients submittedto liver transplantation from 2010 to 2016 of the University Reference Center. The analyzed variables were age, gender,ethnicity, causes that led to liver transplantation, alpha-fetoprotein (AFP) dosage, histological aspects, recurrence,survival and NAFLD. Results: A total of 60 patients were included in the study being 80% men with a mean age of58.3 ± 10.6 years. All patients were cirrhotic. The causes that led to the transplantation were the presence of the hepatitisC virus (HCV) (56.6% of the patients), an association of the virus with alcohol (20%), the presence of the hepatitis Bvirus (HBV) (20%), alcoholic liver disease (ALD) (50.9%) and NAFLD (25%). Of the latter, eight were diagnosedpre-transplantation and seven were NAFLD carriers without a previous diagnosis. Regarding the Edmondson-Steinerhistological classification, 58.5% of the patients were classified as grade ≤ II. Conclusions: There is predominance ofmale patients with a mean age of 58.3 years. Degree ≤ II is the most frequent to the Edmondson-Steiner histologicalclassification in the evaluated casuistic. HCV, ALD and NAFLD is the most common etiological agents found in thestudy. The (high) underestimated prevalence of NAFLD in the pre-transplanted patients is due to the fact that all patientspresented cirrhosis, masking NAFLD signals.     

Biological effects of corosolic acid as an anti-inflammatory,anti-metabolic syndrome and anti-neoplasic natural compound

Accumulating evidence has indicated that corosolic acid exerts anti-diabetic, anti-obesity, anti-inflammatory, anti-hyperlipidemic and anti-viral effects. More importantly, corosolic acid has recently attracted much attention due to its anticancer properties and innocuous effects on normal cells. Furthermore, the increasing proportion of obese and/or diabetic populations has led to an epidemic of non-alcoholic fatty liver disease (NAFLD), which frequently progresses to hepatocellular carcinoma (HCC). Evidence has indicated that NAFLD is closely associated with the development of HCC and comprises a high risk factor. The present review summarizes the anticancer effects of corosolic acid in vitro and in vivo, and its related molecular mechanisms. It also describes the inhibitory effects of corosolic acid on the progression of NAFLD and its associated molecular mechanisms, providing guidance for future research on corosolic acid in NAFLD-related HCC prevention and treatment. To the best of our knowledge, a review of corosolic acid as an anticancer agent has not yet been reported. Due to its multitargeted activity in cancer cells, corosolic acid exerts anticancer effects when administered alone, and acts synergistically when administered with chemotherapeutic drugs, even in drug-resistant cells. In addition, as a novel tool to treat metabolic syndromes, corosolic acid uses the same mechanism in its action against cancer as that used in the progression of NAFLD-related HCC. Therefore, corosolic acid has been suggested as an agent for the prevention and treatment of NAFLD-related HCC.     

Role of caveolin‐1 in hepatocellular carcinoma arising from non‐alcoholic fatty liver disease

The molecular features of hepatocellular carcinoma arising from non‐alcoholic fatty liver disease (NAFLD‐HCC) are not well known. In this study, we investigated the mechanism by which NAFLD‐HCC survives in a fat‐rich environment. We found that caveolin (CAV)‐1 was overexpressed in clinical specimens from NAFLD‐HCC patients. HepG2, HLE, and HuH‐7 HCC cell lines showed decreased proliferation in the presence of the saturated fatty acids palmitic acid and stearic acid, although only HLE cells expressed high levels of CAV‐1. HLE cells treated with oleic acid (OA) showed robust proliferation, whereas CAV‐null HepG2 cells showed reduced proliferation and increased apoptosis. CAV‐1 knockdown in HLE cells attenuated the OA‐induced increase in proliferation and enhanced apoptosis. Liquid chromatography–tandem mass spectrometry analysis revealed that the levels of OA‐containing ceramide, a pro‐apoptotic factor, were higher in HepG2 and CAV‐1‐deficient HLE cells than in HLE cells, suggesting that CAV‐1 inhibits apoptosis by decreasing the level of OA‐containing ceramide. These results indicate that CAV‐1 is important for NAFLD‐HCC survival in fatty acid‐rich environments and is a potential therapeutic target.     

Metabolic syndrome and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Although many risk factors for HCC are well defined, including hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol, most series have indicated that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer. The majority of “cryptogenic” HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome. The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer with respect to both increased risk of disease and worsened outcome. In this review, the authors focused on the relation between metabolic syndrome and HCC. They investigated the increased risks of HCC among individuals with features of metabolic syndrome, potentially worsened cancer outcomes in these patients, possible pathogenic mechanisms to explain these relations, and treatment options for those with NAFLD and its progressive counterpart, nonalcoholic steatohepatitis. It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC. Cancer 2009. © 2009 American Cancer Society.     

“癌症进化发育学”理论进展及其在肝细胞癌靶向/免疫治疗中的作用

原发性肝癌居我国癌症非成熟死亡原因的首位，其中肝细胞癌占93.0%，84.4%是乙肝病毒（HBV）慢性感染所致。在HBV致癌过程中，非可控性炎性反应通过IL-6上调胞苷脱氨酶AID/APOBEC3s家族成员以促病毒和宿主基因变异、下调尿嘧啶DNA糖基化酶（UNG）等降低变异修复，炎性微环境为HBV和人肝细胞的“变异-选择-适应”进化过程提供了必要条件并促进变异细胞逆向分化。该进化过程需满足体细胞驱动突变和免疫抑制微环境这两个前提条件。促癌基因组不稳定和HBV变异通过cGAS-STING抑制Ⅰ型干扰素信号，诱导免疫抑制性炎性反应，招募抑制性免疫细胞如TAMs、Treg、MDSC等构建肿瘤微环境。微环境中肿瘤细胞迅速生长所致的缺氧通过诱导免疫抑制性炎性反应因子激活肿瘤犬尿氨酸代谢，增强Treg的PD-1表达以加强免疫耐受、抑制CD8+T细胞和NK细胞毒性、促进新血管生成。以上“癌症进化发育学”理论为癌症的防治指明了方向。针对新血管生成的靶向治疗能显著遏制肝癌生长、提高抗肿瘤免疫，加强免疫治疗效果。靶向-免疫联合治疗应成为晚期肝癌的主要治疗措施。     

Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8⁺ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8⁺ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8⁺ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.     

Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.     

Immunogenic cell death in colon cancer prevention and therapy

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The colonic mucosa constitutes a critical barrier and a major site of immune regulation. The immune system plays important roles in cancer development and treatment, and immune activation caused by chronic infection or inflammation is well-known to increase cancer risk. During tumor development, neoplastic cells continuously interact with and shape the tumor microenvironment (TME), which becomes progressively immunosuppressive. The clinical success of immune checkpoint blockade therapies is limited to a small set of CRCs with high tumor mutational load and tumor-infiltrating T cells. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, can therefore help break the immunosuppressive TME, engage the innate components, and prime T cell-mediated adaptive immunity for long-term tumor control. In this review, we discuss the current understanding of ICD induced by antineoplastic agents, the influence of driver mutations, and recent developments to harness ICD in colon cancer. Mechanism-guided combinations of ICD-inducing agents with immunotherapy and actionable biomarkers will likely offer more tailored and durable benefits to patients with colon cancer.     

Gut microbiota and immune system in liver cancer: Promising therapeutic implication from development to treatment

Liver cancer is a leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver tumour, followed by cholangiocarcinoma. Notably, secondary tumours represent up to 90% of liver tumours. Chronic liver disease is a recognised risk factor for liver cancer development. Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration. The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota, its metabolites and the liver through the portal flow. The interplay between the immune system and gut microbiota is also well-known. Although primarily resulting from experiments in animal models and on HCC, growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours. Despite the curative intent of “traditional” treatments, tumour recurrence remains high. Therefore, microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment. Furthermore, microbiota could represent a non-invasive biomarker for early liver cancer diagnosis. This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development, focusing on the potential therapeutic implications.     

The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow‐up duration of 6.32 years in the study cohort, the 10‐year cumulative incidence of HCC was 2.73% [95% confidence interval (CI): 1.69–3.76%]. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk [hazard ratio (HR) 6.80, 95% CI: 3.00–15.42; p < 0.001]. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05–1.11) and statin use (HR 0.29, 95% CI: 0.12–0.68) were also identified as independent risk factors. The 10‐year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99–18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0–1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.     

The spatial distribution of immune cell subpopulations in hepatocellular carcinoma

Infiltrating immune cells in the tumor microenvironment (TME) influence tumor progression and patient prognosis, making them attractive therapeutic targets for immunotherapy research. A deeper understanding of immune cell distributions in the TME in hepatocellular carcinoma (HCC) is needed to identify interactions among different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunohistochemistry using a tissue microarray of samples from 302 patients with HCC to elucidate the spatial distributions of immune cell subpopulations (CD3⁺, CD4⁺, CD8⁺, CD66b⁺, and CD68⁺) in HCC and normal liver tissues. We analyzed the associations between different immune subpopulations using Pearson''s correlation. G(r) functions, K(r) functions and Euclidean distance were applied to characterize the bivariate distribution patterns among the immune cell types. Cox regression and Kaplan‐Meier analysis were used to evaluate the associations between tumor infiltration by different immune cells and patient outcomes after curative surgery. We also analyzed the relationship between the spatial distribution of different immune cell subpopulations with HCC patient prognosis. We found that the immune cell spatial distribution in the HCC TME is heterogeneous. Our study provides a theoretical basis for HCC immunotherapy.     

Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1^st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1^st- and 2^nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.     

Non-viral causes of liver cancer: Does obesity led inflammation play a role?

Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation.