Impaired glycoRNA expression may signal liver injury in patients with MASLD

Glycosylated noncoding small RNAs (glycoRNAs) are present in human hepatocytes and liver tissues, showing a dysregulated expression in experimental steatosis models and in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), a study has found.

GlycoRNA presence was detected using northern blot and an imaging approach called sialic acid aptamer and RNA in situ hybridization-mediated proximity ligation assay, which allows direct visualization of glycoRNAs. The investigators also achieved restoration of key mediators of glycoRNA biosynthesis in vivo, using adeno-associated viral vectors (AAV).

GlycoRNAs were found to by synthesized in human liver tissue, primary hepatocytes, and hepatic tumour cells. Most glycoRNA expression was reduced in tissues from patients with MASLD, the most prevalent liver disease worldwide.

Mechanistically, the reduced expression of SID1 transmembrane family member 1 (SIDT1) and DTW domain containing 2 (DTWD2)—two mediators of glycoRNA biosynthesis—contributed to the loss of glycoRNAs in patients with MASLD.

SIDT1 and DTWD2 inhibition elevated fatty acid load in primary human hepatocytes and improved inflammation signals upon co-culture with macrophages. Notably, AAV-mediated in vivo restoration of SIDT1 and DTWD2 resulted in the mitigation of metabolic dysfunction-associated steatohepatitis in mice.

“Furthermore, sequencing of enriched glycoRNA samples identified eight glycoRNAs that were downregulated in steatotic human liver and hepatocytes,” the investigators said.

“[O]ur results suggest that glycoRNA expression is dysregulated in human livers with MASLD, indicating their potential as novel biomarkers of liver injury,” they added.