It takes two to tango: targeting the BMP-SMAD pathway to improve MASLD-MASH and the associated sarcopenia

Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, is frequently associated with obesity and insulin resistance (IR), and affects ~30% of the populations1 . MASLD, defined by an increase in liver fat (>5%), encompasses a spectrum of liver pathology ranging from simple steatosis to steatohepatitis (MASH), characterized by inflammation, fibrotic tissue, with possible evolution to cirrhosis . The molecular mechanisms regulating the development and progression of this multi-organ and multi-factorial disease are still under investigation. Although intense research is ongoing to find drugs that reach the requisites for FDA approval for MASLD, therapeutic opportunities are focused on lifestyle intervention, bariatric surgery or anti-obesity drugs applicable to a minority of patients2 . Skeletal muscle is one of the organs affected by MASLD as it suffers for intramyocellular lipid deposition, inflammation and IR. Vice versa, skeletal muscle metabolism influences MASLD development since muscular atrophy is associated with a poor MASLD prognosis3 . Although the molecular mechanisms linking MASLD and sarcopenia are poorly characterized, hepatokines and myokines might be play a role in the crosstalk between these organs. The BMP-SMAD pathway controls many important biological processes. In hepatocytes and myocytes, this signaling is inhibited by FKBP12 by blocking the function of the BMP type I receptors. This brake is removed by the immunosuppressive drug tacrolimus (TAC), which activates the BMP-SMAD pathway4,5 . Our preliminary data demonstrate the connection between BMP-SMAD pathway, lipid metabolism and muscular function. In vivo and ex vivo hepatocytic lipid accumulation is accompanied by increased FKBP12 expression and downregulation of BMP-SMAD related genes. In the liver, activation of the BMP-SMAD pathway by FKBP12 sequestration upregulates PPARα, a transcription factor that controls lipid and glucose metabolism6 . RNA-seq analysis of liver samples from mice knockdown for Fkbp12 in the hepatocytes shows that genes controlling lipid metabolism are downregulated. Finally, a positive association of FKBP12 with fatty liver (https://maayanlab.cloud/Harmonizome/gene_set/Fatty+Liver/CTD+Gene-Disease+Associations) and immune infiltration in human liver disease7 was found in available datasets and literature, consistent with the proposing role of FKBP12 in MASLD-MASH.