TARGETING THE HEPATIC EPIGENETIC REGULATORS SUV420H1/2 TO COUNTERACT MASLD AND ITS COMPLICATIONS

Several factors contribute to MASLD, including impaired iron metabolism, but the molecular mechanisms involved are still unknown. Notably, a genomic region encompassing the histone methyltransferase Suv420h has been associated with iron-dependent hepatic steatosis in mice, suggesting that epigenetic remodeling plays a role in linking lipid and iron metabolism.

To determine whether Suv420h contributes to MASLD, we compared the differentially expressed signaling pathways in the liver of bariatric patients stratified for Suv420h1-h2 expression. We then generated mice lacking Suv420h1 in hepatocytes and h2 in the whole body (dKO) and characterized them after 16 weeks of a NASH-inducing-diet (FPC).

In bariatric patients, Suv420h1-h2 positively correlated with inflammatory and IFNγ response, and EMT, independently of other confounders. Additionally, in patients expressing higher levels of Suv420h1-h2, overrepresentation analysis indicated enrichment in genes involved in extracellular matrix, collagen fibril organization and leukocyte migration.

In control mice, the FPC diet resulted in mild overweight and hepatomegaly, while dKO were protected and showed less hepatomegaly, fewer lipid droplets, reduced monocyte recruitment, collagen deposition and white adipose tissue hypertrophy. Consistently, liver triglycerides and transaminases were reduced. Liver RNAseq confirmed the protective effect of h1-h2 deletion. FPC-control mice showed increased serum iron and decreased hepcidin. Interestingly, iron parameters normalized in dKO. Pharmacologic targeting of liver h1/h2 by antisense-oligonucleotides in hepatosteatosis confirms their protective role in preventing disease progression.

Suv420h can be considered a promising therapeutic target for MASLD and its complications, including deregulated iron metabolism. Further studies are underway to decipher the signaling pathway modulated by Suv420h1/h2 in hepatocytes.