Prediction of 15-year Risk of MASH (Metabolic Dysfunction-associated Steatohepatitis)-Related HCC (Hepatocellular Carcinoma) by Tissue Proteomic Profiling

Introduction MASH is a progressive liver disease, recognized as a severe form of MASLD, characterized histologically by hepatic steatosis accompanied by hepatocellular inflammation and ballooning degeneration. It represents a growing public health concern due to its strong association with metabolic syndrome components such as obesity, insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. Globally, the prevalence of MASLD is estimated to be approximately 25%, with MASH affecting a substantial subset of these patients, particularly those with comorbid metabolic disorders.

MASH progression is heterogeneous and can lead to advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Importantly, while cirrhosis is a well-known risk factor for HCC, recent epidemiological and clinical studies have demonstrated that HCC can also develop in non-cirrhotic livers affected by MASH. This phenomenon complicates clinical decision-making regarding surveillance and management, as current guidelines primarily recommend HCC screening in patients with cirrhosis regardless of etiology.

The pathogenesis of MASH and its progression to HCC involves complex interactions between metabolic derangements, chronic hepatic inflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, and activation of fibrogenic pathways. Excessive accumulation of free fatty acids and toxic lipid metabolites in hepatocytes induces cellular stress, triggering inflammatory cascades and apoptosis. Kupffer cells and recruited immune cells perpetuate the inflammatory milieu, contributing to progressive fibrosis.

The increasing incidence of MASH-related HCC underscores the urgent need for novel biomarkers capable of accurately stratifying patients according to their risk of HCC development. Early identification of high-risk individuals would allow for tailored surveillance strategies, early diagnosis, and timely therapeutic interventions, potentially improving clinical outcomes. Unfortunately, serological biomarkers, including alpha-fetoprotein (AFP), have limited sensitivity and specificity for early HCC detection in the MASH population. Thus, novel molecular markers reflecting the underlying pathophysiology of MASH and hepatocarcinogenesis are being actively investigated.

Proteomics, the large-scale study of proteins expressed by cells or tissues, offers unique advantages for biomarker discovery in MASH and HCC. Proteins are the functional effectors of cellular processes and may better reflect dynamic pathological changes compared to genomic or transcriptomic data alone.