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) + CCL 4 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.