Metabolic dysfunction-associated fatty liver disease (MAFLD), earlier known as non-alcoholic fatty liver disease (NAFLD), is now a critical global health concern because of its robust association with cancer etiology. Increasing evidence has placed the spotlight on MASLD as a primary causative factor not only for liver cancer but also for extrahepatic cancers. Most importantly, it has been strongly established as a leading risk factor for hepatocellular carcinoma (HCC), the increasing prevalence of which is closely associated with the global increase in metabolic disorders [1]. Its prevalent nature is owed mainly to increasingly sedentary lifestyles, low levels of physical activity, and the chronic intake of high-calorie diets that tend to exceed the body’s energy requirements, especially when linked with poor dietary quality and food imbalance [2]. The defining feature of this condition is the accumulation of fat in the liver in the absence of other contributing factors, such as significant alcohol consumption. Obesity, type 2 diabetes mellitus, and metabolic syndrome have consistently been identified as its primary risk factors [3]. The global surge in obesity and type 2 diabetes has paralleled a sharp rise in the prevalence of MASLD. Recent data indicate that approximately 38% of the adult population is affected, while rates among children and adolescents range between 7% and 14%. Projections suggest that by 2040, nearly 55% of the world’s population could be living with MASLD. Although not every individual with the condition will progress to advanced liver disease, MASLD has nonetheless emerged as the leading indication for liver transplantation in the United States, particularly among women and those diagnosed with hepatocellular carcinoma (HCC) [4]. Although the genetic determinants of hepatic fat accumulation, such as allelic variants of lipid metabolism genes, may also play a role, these are less common and more frequent risk factors such as obesity and components of metabolic syndrome are more frequent. The prevalence of nonalcoholic fatty liver disease (NAFLD) without obesity widely ranges, suggesting that exogenous factors (such as high cholesterol, consumption of sugars such as fructose) and genetic risk factors both contribute to the development of NAFLD, but the latter is not a primary cause [5]. Histologically, NAFLD may be classified into two primary groups: nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL). Lack of hepatic damage, notably ballooning degeneration in hepatocytes, and the buildup of fat in the liver are characteristics of NAFL. NASH, on the other hand, is characterized by hepatic steatosis, inflammation, and visible hepatocyte damage, including ballooning and may occur with or without fibrosis [6].

Even though there is increasing evidence of the association between MAFLD and both hepatic and extrahepatic cancers, several important questions remain unanswered. The majority of the literature remains highly concentrated on HCC, and the potential mechanisms linking MAFLD to cancers beyond the liver are not yet fully understood. It is also challenging to determine causal relationships and patterns of cumulative risk progression, especially in diverse global populations, because large-scale longitudinal studies are seldom available [7]. Unresolved questions include the extend to which disease severity, particularly fibrosis stage, directly impacts cancer incidence, whether MAFLD is an independent driver of carcinogenesis or merely a reflection of underlying metabolic dysfunction, and whether early targeted interventions could potentially significantly reduce future cancer risk in this patient population [8]. The role of MAFLD in clinical response to cancer therapy, and treatment efficacy and outcomes, remain poorly defined, and further mechanistic and clinical research is needed to understand its role [9]. Thus, this review provides a comprehensive summary of the literature on MAFLD and liver-related or extra-hepatic cancers with primary focus on recent knowledge gaps between MAFLD and cancer development, identifies major scientific hurdles as well as clinical needs based on current understanding, and proposes future research directions ranging from molecular mechanisms to advanced risk-stratification models and population-specific longitudinal studies, aimed to developing effective cancer prevention strategies secondary to MAFLD.

The pathogenesis of MASLD is intricate and multifaceted, encompassing fibrogenesis, lipotoxicity, and inflammatory pathways. Following food intake, elevated blood glucose levels stimulate pancreatic insulin secretion; this is an important phase of operation. Then, insulin travels via the portal vein to the liver, where it directs metabolic pathways such as increasing de novo lipogenesis, which converts acetyl-coenzyme A (CoA) into fatty acids, and stimulates glycogenesis, storing excess glucose as glycogen. Activated by insulin, several intracellular signaling pathways mediate these anabolic actions. By managing oxidative metabolism, adenosine triphosphate (ATP) synthesis, and reactive oxygen species production, mitochondria play a crucial part in metabolic regulation. Increased hepatic lipogenesis, decreased insulin signaling in adipose tissue, and increased free fatty acid levels are all consequences of dysregulated anabolic signaling in the setting of hepatic insulin resistance. The development of MASLD is primarily dependent on the accumulation of fatty acids in the liver, which is largely caused by increased lipogenesis triggered by specific transcription factors. Fatty acid β-oxidation, which occurs in the mitochondria of the liver, transforms fatty acids into triglycerides, which are then encapsulated in very-low-density lipoproteins (VLDL) and secreted into the bloodstream. Hepatic steatosis results from triglycerides building up as lipid droplets inside hepatocytes when the capacity for either lipid export or oxidation is surpassed [18]. The development of HCC in MASLD is complicated. Fig. 2 (Ref. [19]) illustrates possible pathways. In liver cells, the accumulation of fat with an underlying lipotoxicity produces a persistent state of inflammation that, over time, leads to fibrosis [19].

Lipid accumulation within hepatocytes characterize both disorders, however, their histological features, propensity for disease development, and clinical prognosis differ significantly. When fat is present in over 5% of hepatocytes without significant inflammation or hepatocellular damage, NAFL is recognized. It has always been thought to be a non-progressive, mostly benign illness. Emerging data, however, casts doubt on this presumption, suggesting that this oversimplified viewpoint could ignore the danger in some subgroups. Particularly in the presence of metabolic comorbidities such as obesity and type 2 diabetes mellitus, between 25–30% of individuals with NAFL may progress to fibrosis and a subgroup to NASH. However, in addition to steatosis, NASH is typified by lobular inflammation and hepatocyte damage, including ballooning degeneration. This kind of illness has a much higher chance of developing cirrhosis, severe fibrosis, and HCC. It has been determined that the degree of fibrosis is the most accurate indicator of liver-related morbidity and overall mortality among several histological characteristics. Since a liver biopsy is now required for a definite diagnosis, distinguishing between NAFL and NASH is still clinically difficult. Disease monitoring and risk assessment are made more difficult by the fact that non-invasive diagnostic techniques still lack the sensitivity and specificity to reliably differentiate between the two. Advancing research identifies the wider systemic effect of NAFLD, which indicates that even individuals with uncomplicated steatosis are susceptible to drug-induced liver damage, alcoholic liver injury, and cardiovascular disturbances likely due to underlying hepatocellular dysfunction [20].

MASLD has been the fastest-increasing cause of HCC globally. A Swedish population-based study is presented as recent evidence that MASLD has surpassed conventional causes of hepatitis C virus (HCV) infection as the leading cause of HCC in Sweden. Between 2012 and 2018, the incidence of MASLD-related HCC increased markedly, rising by 50% from 1.0 to 1.5 cases per 100,000 person-years. By 2017, MASLD accounted for 22% of all diagnosed cases of HCC in Sweden, overtaking HCV as the most common underlying cause. The declining prevalence of viral hepatitis due to successful antiviral therapy and the rising global prevalence of obesity, type 2 diabetes, and metabolic syndrome are two of the large burden diseases with a high risk of MASLD, and are only two illustrations of the broader shifts in disease epidemiology underlined by this trend. The study found that 39% of MASLD related HCC did not have cirrhosis, which is particularly clinically relevant. The exclusion of non-cirrhotic people from existing monitoring techniques usually results in delayed diagnosis, a higher tumor burden, and limited access to curative treatment choices, which makes this study noteworthy. Although early-stage detection rates (Barcelona Clinic Liver Cancer (BCLC) stage 0–A) were similar, individuals with MASLD-HCC were often older (median age of 75), had bigger tumors, and had a greater risk of extrahepatic metastases than patients with HCC from other sources. Relative to their non-MASLD counterparts, a lower percentage of MASLD-HCC patients received curative therapy; however, after controlling for confounding factors, adjusted multivariable analysis showed no statistically significant differences in outcomes. The need to develop more comprehensive monitoring systems and improve HCC risk classification is highlighted by these findings, especially for MASLD, those who have no evidence of cirrhosis but are nonetheless at high risk for liver cancer [21].

The research, “miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression”, examines the molecular and genetic pathways responsible for the progression of hepatocellular carcinoma (HCC) from MASLD. This study examines the role of microRNA-33 (miR-33) because it has been identified as a key regulator of liver disease development from metabolism. Hepatocellular carcinoma (HCC) and liver fibrosis are serious outcomes of the most common liver disease, known as MASLD. Researchers reported that miR-33 levels were demonstrably elevated in the livers of MASLD patients and in animals used in experiments. The authors made a miR-33 knockout mouse model in hepatocytes available for a deeper understanding as well. The miR-33 knockout mice exhibited some significant metabolic disruptions, such as inhibiting liver fat condensation, promoting reduced inflammation, and limiting fibrotic developments. The cellular consequences of the knockdown of miR-33 included inhibition of lipogenesis, stimulation of mitochondrial biogenesis, and stimulation of fatty acid oxidation. It also upregulated genes involved in cholesterol regulation and antioxidant defense, and downregulated pathways of liver damage and injury. It is interesting to note that deletion of miR-33 downregulates the yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) signaling pathway, which is a major driver of liver cancer development. Long-term experiments demonstrated a significant reduction in liver tumors in miR-33-deficient mice, in addition to inhibition of tumor growth and cell proliferation. Overall, miR-33 is a molecular link between metabolic liver disease and cancer and represents a potential therapeutic target for preventing MASLD-associated HCC [22]. The majority of existing data on miR-33 in NAFLD comes from preclinical models. For example, in fructose-fed mice, hepatic miR-33 is altered, and functional studies are performed using in vitro [23].

Through an integrated analysis of RNA sequencing states and whole-exome sequencing of liver tissues from patients with MASLD, three distinct transcriptomic subtypes (G1–G3) have been identified, which reflect differences in the stage of disease progression. The IFI16 gene variant (rs6940, A>T, portending a missense mutation T779S), represents an important factor associated with worsening disease severity. This variant enhances inflammatory responses through DNA-sensing, specially via the interferon gamma inducible protein 16 IFI16-PYCARD (adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD))-protease enzyme Caspase-1 (CASP1) signaling pathway, which can act as a biomarker of disease progression for MASLD [24]. In relation to IFI16, the data is more in the early stages. A very recent integrative genomic/transcriptomic study in MASLD liver tissue reported that genetic variants for IFI16 (rs6940) had associations with disease progression, and that in vitro binding assessments indicated the variant had stronger dsDNA binding and increased inflammatory signaling through the IFI16-PYCARD-caspase-1 pathway [24]. Next-generation sequencing (NGS) and artificial intelligence (AI) advancements are revolutionizing the diagnosis and management of HCC. Alpha-fetoprotein (AFP) testing and ultrasound imaging are traditional methods that have been undervalued, as they are not sensitive, particularly at the earlier stages of disease detectable by the testing modalities. NGS allows for the capacity of identifying a genetic mutation in somatic blood or tissue to allow early diagnosis. In particular, non-invasive liquid biopsies (specifically those making the distinction between circulating tumor DNA and cfDNA) are being increasingly recognized for their reliable potential for the early, accurate diagnosis as technologists increasingly trust the sufficiency of the data. Commercially available platforms such as Foundation One Liquid CDx and Guardant360 CDx, now provide timely, safe, and more precise alphanumeric characterization results. In addition to diagnosis, NGS also identifies molecular biomarkers, which are crucial for personalized treatment. NGS makes it possible to identify resistance-associated mutations in viral hepatitis, such as Hepatitis B Virus (HBV) and HCV (e.g., G1896A in HBV; (Nonstructural protein 5A) NS5A and NS5B mutations in HCV), which helps choose antiviral treatments that work.

Furthermore, changes in Tumor Protein p53 (TP53), Telomerase Reverse Transcriptase (TERT), and Catenin Beta 1 (CTNNB1) are examples of recurrent somatic mutations in HCC that have therapeutic and prognostic consequences. For example, CTNNB1 mutations may indicate resistance to immunotherapy, especially immune checkpoint drugs, but TP53 mutations are frequently linked to poor clinical outcomes. Through the analysis of intricate genomic datasets, AI greatly enhances the usefulness of NGS by identifying molecular patterns and mutations that are clinically significant. Invasive treatments are frequently avoided because of AI-based diagnostic algorithms that improve early detection and make accurate variant calling possible. The integration of NGS with AI thus supports a precision oncology framework, allowing for more tailored treatment plans and better patient outcomes [25].

Several recent investigations have aimed to delineate the differences between patients with and without cirrhosis regarding the incidence and clinical outcomes of HCC developing in association with MASLD. Nearly 35% of cases of HCC associated with MASLD develop in non-cirrhotic livers, according to data from a multicenter registry. The non-cirrhotic MASLD-related HCC patients tend to have larger tumor sizes (as well as more advanced stages of disease) and were often older at diagnosis compared to cirrhotic patients, but also had better liver function, with the consideration that they may receive more aggressive and potentially curative therapies. Since HCC typically presents incidentally in non-cirrhotic patients, they are not routinely surveilled, and as such, their diagnosis is generally at a later stage of disease than their cirrhotic counterparts. As a result of their higher hepatic functional reserve, non-cirrhotic MASLD patients can achieve survival outcomes similar to patients with cirrhosis, even if they tend to have a greater burden of tumor [23, 24]. In addition, research shows that while the overall incidence of HCC in MASLD patients without cirrhosis is low (<1.5 cases per 1000 patient years), it is still clinically relevant, given how common MASLD is worldwide [23]. Although the primary aim of present screening initiatives is aimed at cirrhotic patients, this distinction has significant consequences for surveillance approaches. Robust predictive models and extensive cost-benefit analyses are needed to adequately incorporate non-cirrhotic MASLD [25]. Table 1 (Ref. [21, 26, 27, 28, 29]) summarizes key studies detailing the study type, country, duration, and major findings, providing an evidence-based overview of the oncogenic risk associated with MASLD.

Median survival is often less than 12 months, underscoring the importantce to monitor people, especially those at higher risk, such as those with cirrhosis or chronic HBV infection. Because of this, the latest guidelines from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend getting liver ultrasounds every six months, sometimes combined with alpha-fetoprotein tests. Even though there is no level I evidence supporting this approach, many observational studies have shown that regular monitoring works well for people with cirrhosis. Also, randomized controlled trials have confirmed that surveillance is helpful for those with HBV [30].

One of the biggest causes of cancer-related death around the world is still HCC, particularly among individuals with cirrhosis. Improving clinical outcomes requires routine surveillance because it makes early tumor diagnosis possible, which is necessary for access to potentially curative treatments such as radiofrequency ablation, liver transplantation, and surgical resection. An extensive meta-analysis that included 47 studies and more than 15,000 patients showed that surveillance greatly raises the chances of finding HCC early (odds ratio (OR) = 2.08) and getting treatment for it (OR = 2.24). Crucially, even after correcting for lead-time bias, patients who received routine surveillance also had improved overall survival (OR = 1.90). The difference in prognosis is remarkable: 5-year survival rates for early-stage HCC treated with curative intent can reach 70%, while advanced-stage disease usually has a median.

Therapeutic approaches for MASLD are evolving rapidly, with some of the current approaches involving modification of metabolic risk factors, new pharmacotherapy approaches, and intervention studies targeting risk factors implicated in the progression of disease [31]. As research progresses into the MASLD metabolic, inflammatory, and fibrotic mechanisms, the therapeutic options available to manage MASLD continue to evolve. Current strategies include lifestyle modification, metabolic options, and most current work in pharmacological, molecular, and/or nano-technology therapeutics. The goal of these interventions is to reduce steatosis and inflammation, and halt the fibrosis and progression of long-term disease.

Flavonoids have proven to be synergistic with traditional chemotherapeutic agents to improve drug effectiveness and to target drug resistance. For example, quercetin has been shown to improve the anticancer ability of 5-fluorouracil and docetaxel, and epigallocatechin gallate (EGCG) improves the cytotoxicity of doxorubicin and gemcitabine. These combinations can lead to improved treatment outcomes while allowing dose reduction to minimize side effects. Recent studies have verified that targeting the ferroptotic pathway may impede the advancement of MASLD. Drugs like the thiazolidinediones (pioglitazone), Glucagon-like peptide-1 (GLP-1) receptors agonists (liraglutide), and a myriad of nutraceuticals including vitamin E, curcumin, quercetin have been found to have examples of anti-ferroptotic activity. These agents have been utilized to target the ferroptotic process through different mechanisms, including inhibitors of acyl-CoA synthetase long-chain family member 4 (ACSL4), activators of glutathione peroxidase 4 (GPX4), and/or stimulators of the Nrf2 antioxidant system. Their ability to modify iron homeostasis, inhibit oxidative stress-related damage, and to inhibit lipid peroxidation validates their influence as broad-spectrum treatment options for target MASLD.

In the future, perhaps our treatment response exploration will include ferroptosis-related biomarkers as a part of clinical trials. It is also important to gain a better understanding of the molecular processes, especially surrounding Factory X Racewear (FXR), AMPK, and mitochondrial factors. It may be possible to find novel treatment targets by identifying ferroptosis modulators in hepatic and extrahepatic tissues (such as adipose tissue and pancreatic β-cells). Additional clinical benefits may be provided by combination treatments that target inflammation, lipid metabolic abnormalities, and iron dysregulation. The application of AI-driven drug discovery techniques and delivery methods based on nanotechnology has the potential to speed up the creation of optimal medicines that target ferroptosis [40]. However, one of the main challenges with ferroptosis-based therapies is that most of the evidence comes from preclinical studies (animal or cell models), and the best options for precisely regulating ferroptosis across the different stages of NAFLD are not well understood, which limits the translation of preclinical studies to human studies [41]. Similarly, in AI-based therapeutic (or prognostic) approaches to liver disease (including MASLD), the hurdles included small and not representative datasets, not externally validated, algorithm transparency, and data integration and privacy issues, all of which limit real-world clinical use [42]. Nonetheless, predictive medicine is changing quickly due to AI and machine learning (ML), especially in detecting high-risk MASLD patients who could develop HCC. Early and precise risk stratification is crucial because MASLD can develop into HCC without obvious clinical symptoms, particularly when severe fibrosis or cirrhosis is not present. Conventional screening methods frequently fail to identify at-risk people in these early, asymptomatic phases. A solution is provided by ML-based models, which use a variety of clinical and laboratory factors to produce individualized risk assessments. A recent study utilizing data from UC Davis and UC San Francisco developed a predictive model for HCC in patients with MASLD, achieving remarkable accuracy of 92.06% and an AUC of 0.97. Among the various clinical variables, the Fibrosis-4 (FIB-4) score emerged as the most influential predictor, followed by bilirubin, alkaline phosphatase (ALP), total cholesterol, and the presence of hypertension. The research underscored the power of ensemble learning algorithms like random forests and gradient boosting to handle complicated, nonlinear medical data, superior to other methods.

Future enhancements will come from integrating predictive systems with heterogeneous data sets; for example, in the future, predictive systems will utilize genomic data, imaging studies, environmental exposures, and lifestyle variables to perform risk stratification. Robust validation in real-world clinical practices and in ethnically diverse populations will be needed. Incorporation of these AI-based models into electronic medical record (EMR) systems could provide real-time risk stratification and inform population-level screening as well as tailored recommendations for individual patients [43].

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has become recognized as an important global health problem because of its strong relationship with hepatocellular carcinoma (HCC). MASLD is mainly induced by the triad of obesity, type 2 diabetes, and physical inactivity, ranging from simple steatosis to NASH continuing through to fibrosis, cirrhosis, and liver cancer. One of the important clinical obstacles is that MASLD-associated HCC often develops in non-cirrhotic livers, making early-stage detection particularly difficult. This disease is developed by multifactorial mechanisms, such as insulin resistance, lipid accumulation, oxidative stress, mitochondrial dysfunction, and chronic inflammatory response. Recent advances in transcriptional and post-transcriptional processes have strengthened current understanding of carcinogenic pathways, with the participation of miR-33 and IFI16 splice variants. Non-invasive diagnostic approaches, including liquid biopsies, next-generation sequencing (NGS), and AI-based risk prediction approaches, are becoming increasingly established tools for early detection as well as personalized surveillance. Therapeutic approaches are developing, with particular focus on ameliorating oxidative stress, fibrosis, inflammatory pathways, and lipid dysregulation, as well as targeting bioactive flavonoids, repurposed drugs (i.e., metformin and statins), and delivery systems in the form of nanotechnology. In conclusion, the treatment of MASLD and its oncogenic risks needs a precision-medicine strategy combining dietary and lifestyle interventions, targeted anti-pharmacotherapy, as well as an innovative diagnostic tool.