Yin Yang Interactomes Drive the Metabolic Dysfunction-Associated Liver Disease Continuum to Hepatocellular Carcinoma

The risk for hepatocellular carcinoma (HCC) arising from metabolic dysfunction– associated steatotic liver disease (MASLD)–related cirrhosis exceeds the risk for cancer developing in the kidney, heart, or lung as a consequence of end-stage disease in those organs. Both experimental and clinical studies support the existence of circulating biomarkers whose elevated expression is associated with, and supports the diagnosis of, HCC. We posit the existence of oncogenic HCC biomarkers under regulation by tumor-suppressive microRNAs (miRs), and that reduced tumor-suppressive miR expression leads to increased oncogenic biomarker expression. By interrogating the MASLD–HCC miR interactome and miRs known to regulate HCC biomarkers, we identified hsa-miR-577, hsa-miR-9500, hsa-miR-101-3p, miR-206, hsa- miR-219a-1-3p, and hsa-miR-613 as tumor-suppressive miRs whose expression is reduced across multiple cancers. Their target genes, osteopontin, Golgi protein-73, and Dickkopf-related protein 1, exhibit increased expression in HCC and display oncogenic activity. Collectively, dysregulated expression of these miRs and their downstream gene products may contribute to progression along the MASLD continuum toward HCC. Highlights We identified tumor suppressive miRs, hsa-miR-577, hsa-miR-9500, hsa-miR-101-3p, miR-206, hsa-miR-219a-1-3p, and hsa-miR-613 with potentially reduced expression levels in HCC. Their gene products, osteopontin, Golgi protein-73, and Dickkopf-related protein 1, exhibit oncogenic properties and increased expression levels in HCC. These miR-gene product interactions may drive the MASLD continuum to HCC. Mechanistic insights should illuminate therapies. Identification of therapeutics that interrupt these interactions may represent a therapeutic pillar for patients with MASLD. Figure MASLD-related HCC. The intersection set between the MASLD-HCC miR interactome and the set of miRs regulating biomarkers diagnostic for HCC was interrogated and tumor suppressive miRs regulating HCC biomarkers with oncogenic activity were identified. Increased risk for HCC in patients with MASLD and MASLD-cirrhosis may arise from interactions between these dysregulated miRs and their downstream gene products. Prologue Metabolic Dysfunction-Associated Liver Disease (MASLD), the leading cause of hepatocellular carcinoma (HCC) in Sweden, is now taking epidemic proportions in South Asia. In India, there is a relatively high prevalence of pre-diabetes, diabetes and insulin resistance; body mass indices > 35 are being observed. Each of these and/or their combinations represent risk factors for MASLD. Nevertheless, both patients and providers are largely oblivious to this disease, both from a lack of general awareness and the asymptomatic nature of MASLD, at least early within its continuum. Diagnosis is often made late, and by exclusion, when presentation may include fatigue, drowsiness, mild encephalopathy (MASLD-pituitary feedback loop), prominent hepatomegaly and asciites, and with liver-specific test demonstrating stiffness, scarring and even HCC. Societal awareness and effective management of this disease are urgent needs. A strategy akin to the 4 pillars for treatment of type 2 diabetes and chronic kidney disease (CKD) needs to be implemented for treatment of patients with MASLD. Figure Four-pillar Strategy for MASLD. A strategy akin to the one in place for treatment of type 2 diabetes and CKD needs to be implemented for treatment of patients with MASLD. Aspects of this strategy, viz. SGLT2i and GLP-1±GIP agonists, are already approved in MASLD.