MicroRNA-122 as a regulator and biomarker of liver disease

Abstract

MicroRNA-122 (miR-122) is the most abundant liver-specific microRNA, comprising ~ 70% of the hepatic miRNA pool, and a central regulator of lipid metabolism, inflammation, fibrosis, viral replication, and hepatocarcinogenesis. This review synthesizes experimental, clinical, and molecular evidence on the role of miR-122 across the spectrum of liver disease, including metabolic dysfunction-associated fatty liver disease (MAFLD) and steatohepatitis (MASH), drug-induced acute liver injury, hepatitis B and C virus (HBV/HCV) infection, hepatocellular carcinoma (HCC), and colorectal cancer liver metastasis. Mechanistically, miR-122 governs hepatic lipogenesis through the Sirt1/LKB1/AMPK axis, modulates inflammation via LPS/TLR-4/FoxO3 signaling, and exerts tumor-suppressive and antiviral effects through Cyclin G1/p53, HO-1, NDRG3, GALNT10, PEG10, and NEGR1. A recurring theme is the compartment- and stage-dependent behavior of miR-122: hepatic expression declines with disease progression, whereas circulating levels rise with hepatocyte injury, reconciling apparently contradictory reports and underscoring the importance of specimen source and disease stage in biomarker interpretation. We further contrast the etiology-specific regulation of miR-122 in HBV- versus HCV-associated disease, in which epigenetic silencing and interferon-linked mechanisms drive divergent expression. Finally, we critically appraise the failed clinical translation of anti-miR-122 therapeutics (miravirsen, RG-101), highlighting viral resistance, safety liabilities, and the tumor-suppressor paradox that constrains inhibition-based strategies. Collectively, miR-122 emerges as a minimally invasive biomarker and a biologically informative, though therapeutically challenging, target in liver disease. Master Liver Regulator: miR-122 is the most abundant liver-specific miRNA, essential for regulating metabolism, inflammation, and cell integrity. Its disruption is a central event in diseases like MAFLD, viral hepatitis, and liver cancer. Sensitive Injury Gauge: Circulating miR-122 is a sensitive, non-invasive biomarker that directly reflects hepatocyte damage, outperforming traditional enzymes in tracking liver injury severity. Viral Infection Paradox: miR-122 plays opposing roles in viral hepatitis: it is essential for HCV replication but acts as an antiviral tumor suppressor in HBV, where its loss promotes cancer. Cancer Driver & Guardian: In hepatocellular carcinoma (HCC), loss of miR-122 is a key event driving tumor growth and metastasis. Its expression patterns differ between HBV-driven and HCV/MASLD-driven cancers. Therapeutic Crossroads: While inhibition of miR-122 successfully treated HCV, long-term safety concerns halted development. Current focus has shifted to exploring its restoration as a therapy for MASLD and HBV-related HCC, though delivery remains a challenge. Master Liver Regulator: miR-122 is the most abundant liver-specific miRNA, essential for regulating metabolism, inflammation, and cell integrity. Its disruption is a central event in diseases like MAFLD, viral hepatitis, and liver cancer. Sensitive Injury Gauge: Circulating miR-122 is a sensitive, non-invasive biomarker that directly reflects hepatocyte damage, outperforming traditional enzymes in tracking liver injury severity. Viral Infection Paradox: miR-122 plays opposing roles in viral hepatitis: it is essential for HCV replication but acts as an antiviral tumor suppressor in HBV, where its loss promotes cancer. Cancer Driver & Guardian: In hepatocellular carcinoma (HCC), loss of miR-122 is a key event driving tumor growth and metastasis. Its expression patterns differ between HBV-driven and HCV/MASLD-driven cancers. Therapeutic Crossroads: While inhibition of miR-122 successfully treated HCV, long-term safety concerns halted development. Current focus has shifted to exploring its restoration as a therapy for MASLD and HBV-related HCC, though delivery remains a challenge.