Long non-coding RNA LINC00885 contributes to liver steatosis through modulation of DHRS2-associated lipid metabolic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and rising liver disease. Its inflammatory subtype, metabolic dysfunction-associated steatohepatitis (MASH), can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. The role of long intergenic non-protein coding RNA 885 (LINC00885) in MASLD remains unknown. This study aims to clarify its function in steatotic liver disease.

Public liver transcriptomic datasets, RNA sequencing of LINC00885-knockdown Hep G2 cells, and microarray profiling under lipotoxic conditions were integrated to identify candidate downstream components. Gain- and loss-of-function models, Oil Red O staining, RT-qPCR, an actinomycin D chase assay, functional rescue, and JC-1 analysis were used to evaluate the LINC00885-DHRS2 axis. Circulating exosomal RNA and exploratory ROC analyses were assessed in a pilot cohort.

LINC00885 was upregulated in MASH liver tissue and induced by FFA treatment in hepatocytes. LINC00885 promoted lipid accumulation and shifted lipid metabolic gene expression toward lipogenesis. Integrated transcriptomic analyses identified DHRS2 as a convergent downstream candidate. LINC00885 knockdown increased DHRS2 expression and was associated with slower DHRS2 mRNA decay. DHRS2 exerted an anti-steatotic phenotype, and DHRS2 depletion reversed the reduction in lipid accumulation caused by LINC00885 knockdown. DHRS2 perturbation was also accompanied by changes in mitochondrial membrane potential. In a pilot serum cohort, exosomal LINC00885 and DHRS2 showed opposite expression patterns and preliminary discriminative potential.

The findings support a functional LINC00885-DHRS2 axis associated with hepatocellular lipid accumulation, lipid metabolic gene expression, and mitochondrial membrane potential. The circulating exosomal observations are exploratory and require validation in larger, clinically characterized cohorts.