The oncogenic implications of metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), is receiving growing attention as a major public health issue globally, primarily because of its association with the development of hepatocellular carcinoma (HCC). MASLD is predominantly caused by obesity, type 2 diabetes mellitus, and lack of exercise, and has a broad clinical spectrum ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately HCC. The pertinent problem is that HCC due to MASLD typically develops in patients without cirrhosis, making diagnosis and follow-up exceedingly challenging. MASLD is described as a multi-faceted condition involving insulin resistance, lipid deposition, oxidative stress, and chronic inflammation. Recent molecular studies related to lipid metabolism, mitochondrial dysfunction, and oncogenic pathways have identified candidate molecules, including microRNA-33 (miR-33), and Interferon Gamma Inducible Protein 16 (IFI16) variants. Emerging non-invasive diagnostic technologies, including liquid biopsies, next-generation sequencing (NGS), and machine learning-based models, are becoming important for early detection and individualized risk assessment. Currently, therapeutic interventions target oxidative stress, inflammatory responses, fibrosis, and lipid dysregulation. Some of the potentially useful interventions include bioactive flavonoids, repurposed medications (metformin and statins), and a novel nanotechnology-based drug delivery system that could slow disease progression and reduce cancer risk. Treating MASLD while addressing the risk of malignancy will require a precision medicine approach with a focus on lifestyle intervention, directed pharmacotherapy, and advanced diagnostic approaches implemented in a multidisciplinary fashion.