miR-210-3p Ameliorates Metabolic Dysfunction-Associated Steatohepatitis-Related Fibrosis by Targeting ISCU and Induces Ferroptosis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis plays an important role in MASH prognosis; however, the underlying mechanism remains unknown. Here, we explored the involvement of miR-210-3p in MASH-associated fibrosis.

METHODS

We examined miR-210-3p expression in patients with MASH, with or without fibrosis using microarray analysis. miR-210-3p expression both in vivo and in vitro was validated using real-time quantitative reverse transcription PCR (RT-qPCR). Target genes and mechanisms were explored using western blotting, dual luciferase assay and immunofluorescence staining. Ferroptosis was assessed based on the levels of malondialdehyde (MDA), glutathione (GSH), iron and ferroptosis-related protein.

RESULTS

miR-210-3p decreased significantly in mice fed methionine-choline-deficient (MCD)-fed and in those fed a high-fat diet (HFD) + CCL4 diets. Palmitic acid (PA)-stimulated LX2 and primary hepatic stellate cells showed miR-210-3p downregulation, consistent with the microarray results. miR-210-3p overexpression alleviated MASH-related fibrosis by inducing ferroptosis in hepatic stellate cells. Iron-sulfur cluster assembly enzyme (ISCU) was validated as the downstream target of miR-210-3p and its overexpression reversed miR-210-3p-induced ferroptosis. Overall, the ISCU-IRP1-CD71 axis is vital to miR-210-3p-induced ferroptosis.

CONCLUSIONS

miR-210-3p expression is decreased in MASH-related fibrosis and is involved in ferroptosis by targeting ISCU.