Activated hepatic stellate cell-derived exosomal miR-23a-3p promotes hepatocellular carcinogenesis by regulating...

Activation of hepatic stellate cells (HSCs) is a core driver of liver fibrosis and may contribute to the evolution to hepatocellular carcinoma (HCC). Exosomes mediate intercellular signaling by transporting bioactive molecules, yet the role of activated HSC-derived exosomes in hepatocarcinogenesis remains unexplored.

This study aims to investigate whether and how activated HSCs induce hepatocarcinogenesis through the mediation of exosomes.

Exosomes from activated HSCs were isolated and applied to hepatocytes to assess malignant transformation via immunoblotting, soft-agar colony formation, and xenograft assays. Oncogenic miRNAs were screened by sequencing and validated by qPCR. Target genes and signaling pathways were identified through transcriptomics, bioinformatics, and dual-luciferase assays. Functional roles of miRNAs and downstream pathways were confirmed via gain/loss-of-function experiments. Clinical correlations and diagnostic potential of exosomal miRNAs were evaluated using patient samples.

Exosomes from activated HSCs induced hepatocyte malignant transformation in vitro and tumorigenesis in vivo. MiR-23a-3p was markedly enriched in activated HSC-derived exosomes and exerted oncogenic effect upon delivery to recipient hepatocytes. Mechanistically, exosomal miR-23a-3p directly targeted DUSP5 in hepatocytes, thereby suppressing its expression and subsequently activating pro-oncogenic ERK signaling. Notably, the miR-23a-3p/DUSP5/ERK signaling axis exhibited progressive activation that paralleled histopathological transitions from fibrosis to HCC in both murine models and clinical specimens. Clinically, elevated plasma exosomal miR-23a-3p levels demonstrated significant diagnostic merit for detecting precancerous lesions and predicting HCC onset in patient cohorts.

Our results indicate that activated HSCs secrete exosomes enriched with miR-23a-3p, which directly target to inhibit DUSP5, and subsequently activate ERK signaling in hepatocytes, leading to the initiation of cellular malignant transformation and tumorigenesis.