Activation of the BMP-SMAD pathway counteracts MASLD and its complications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, which is characterized by fat accumulation and insulin resistance and can progress to steatohepatitis. Excess iron in hepatocytes favors MASLD, suggesting that lipid and iron metabolism are linked. The hepatic BMP-SMAD-pathway controls systemic iron homeostasis. In this context, two inhibitors of the BMP-SMAD-pathway, the TMPRSS6 and the immunophilin FKBP12, have been described. Our unpublished in vitro and in vivo data have shown that upregulation of BMP-SMAD-pathway activates the peroxisome-proliferator-activated-receptor (PPAR)α, suggesting a link between iron and lipid/glucose metabolism. In addition, the expression of key components of BMP-SMAD-pathway as well as hepcidin is reduced, while FKBP12 is upregulated in the liver of MASLD mouse model, suggesting that suppression of hepatic BMP-pathway and altered iron homeostasis are responsible for disease progression.

For these reasons, we hypothesize that activation of the BMP-SMAD-pathway may be a potential therapeutic approach for this disease. To this end, wild-type mice were fed a fructose-palmitate-cholesterol (FPC) diet that induces hepatic steatosis, inflammation and fibrosis, recapitulating the main features of the human disease. When hepatosteatosis was established, the liver BMP-SMAD-pathway was upregulated by antisense oligonucleotides (ASOs) targeting TMPRSS6. Treatment with Tmprss6-ASO counteracts FPC-induced hepatomegaly, ameliorates hepatosteatosis, and reduces hepatic triglyceride accumulation and expression of genes involved in lipid storage and de novo lipogenesis. Moreover, hyperactivity of the BMP-SMAD-pathway decreases the expression of pro-inflammatory cytokines and prevents collagen deposition and fibrosis. Overall, these data show that pharmacological activation of the BMP-SMAD signaling pathway improves MASLD.