MASLD and Cancer Risk: Pathogenic Links and Clinical Implications Reviewed

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has emerged as a global health epidemic, paralleling the rise in obesity, type 2 diabetes, and metabolic syndrome. Beyond its well-documented progression to cirrhosis and hepatocellular carcinoma (HCC), growing evidence suggests that MASLD is independently associated with an increased risk of extrahepatic malignancies, including colorectal, breast, and pancreatic cancers. This review explores the complex interplay between MASLD and carcinogenesis, focusing on underlying mechanisms, epidemiological associations, and clinical implications for early detection and prevention.

MASLD: Definition, Prevalence, and Progression

MASLD is defined by hepatic steatosis in the absence of significant alcohol consumption, accompanied by at least one feature of metabolic dysregulation such as obesity, insulin resistance, or dyslipidemia. It encompasses a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and eventually cirrhosis. With a global prevalence exceeding 25%, MASLD is now the most common chronic liver disease worldwide. Importantly, even early-stage MASLD—without advanced fibrosis—has been linked to elevated cancer risk, suggesting that metabolic derangements, rather than just liver damage, play a key role in oncogenesis.

Epidemiological Links Between MASLD and Cancer

Large cohort studies and meta-analyses have consistently demonstrated that MASLD is associated with a 1.5- to 2-fold increased risk of HCC, independent of cirrhosis. Notably, MASLD also correlates with higher incidence rates of extrahepatic cancers, particularly gastrointestinal (colorectal, gastric), hormone-sensitive (breast, prostate), and obesity-related malignancies (endometrial, renal). For example, a 2023 meta-analysis found that MASLD patients had a 56% higher risk of colorectal cancer, likely due to shared risk factors such as insulin resistance and chronic inflammation. These associations persist even after adjusting for confounding metabolic comorbidities, underscoring MASLD as an independent risk factor.

Mechanistic Insights: How MASLD Drives Carcinogenesis

The oncogenic potential of MASLD stems from multiple interconnected pathways. Insulin resistance and hyperinsulinemia activate proliferative signaling via the IGF-1/PI3K/AKT/mTOR axis, promoting tumor growth in both hepatic and extrahepatic tissues. Chronic low-grade inflammation, driven by adipose tissue dysfunction and hepatocyte lipotoxicity, leads to elevated pro-inflammatory cytokines (TNF-α, IL-6) and oxidative stress, which damage DNA and foster a tumor-permissive microenvironment. Additionally, gut dysbiosis—a hallmark of MASLD—increases intestinal permeability, allowing bacterial endotoxins (e.g., lipopolysaccharide) to enter the portal circulation and further exacerbate hepatic and systemic inflammation.

MASLD and Hepatocellular Carcinoma: A Unique Pathogenesis

Unlike viral hepatitis-related HCC, which typically arises in cirrhotic livers, MASLD-associated HCC can develop in non-cirrhotic livers, highlighting the role of metabolic dysregulation. Key mechanisms include lipotoxicity-induced hepatocyte injury, activation of fibrogenic pathways (TGF-β, hedgehog signaling), and epigenetic modifications that silence tumor suppressor genes. Emerging evidence also implicates alterations in bile acid metabolism and immune surveillance (e.g., impaired NK cell function) in MASLD-driven hepatocarcinogenesis. These findings underscore the need for vigilant cancer surveillance in MASLD patients, even in the absence of advanced fibrosis.

Clinical Implications: Screening and Risk Mitigation

Given the heightened cancer risk in MASLD patients, clinicians should adopt a proactive approach to surveillance. Regular HCC screening (ultrasound ± AFP) is recommended for those with advanced fibrosis, though debates persist about extending surveillance to non-cirrhotic MASLD. For extrahepatic cancers, tailored strategies—such as earlier/frequent colonoscopy in MASLD patients with metabolic syndrome—may be warranted. Lifestyle interventions (weight loss, Mediterranean diet, exercise) remain cornerstone therapies, as even modest weight reduction (7–10%) improves steatosis and reduces inflammatory markers. Pharmacological agents like GLP-1 receptor agonists and SGLT2 inhibitors, which ameliorate insulin resistance, may also mitigate cancer risk, though long-term data are awaited.

Future Directions and Unanswered Questions

Critical knowledge gaps remain, including whether MASLD treatment (e.g., with FXR agonists or antifibrotics) reduces cancer incidence and whether specific MASLD phenotypes (e.g., lean MASLD) confer differential risk. Prospective studies exploring multi-omics signatures (metabolomic, microbiome) could identify high-risk subgroups for personalized prevention. Additionally, the role of MASLD in cancer treatment outcomes—such as immunotherapy response in HCC—warrants further investigation.

Conclusion

MASLD is not merely a liver-specific disorder but a systemic metabolic condition with far-reaching oncogenic consequences. Its association with both hepatic and extrahepatic malignancies underscores the importance of multidisciplinary care integrating hepatology, oncology, and endocrinology. By recognizing MASLD as a modifiable cancer risk factor, clinicians can implement early interventions to disrupt carcinogenic pathways and improve patient outcomes. Future research should prioritize mechanistic studies and randomized trials to refine risk stratification and therapeutic strategies in this high-risk population.

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