To test the therapeutic potential of FSP27-based therapies on the regression of preexistent NASH, herein we defined the consequences of long-term therapeutic silencing of Fsp27 using generation 2.0 antisense oligonucleotides (ASOs), alone or in combination with the PPARα agonist fenofibrate, on the progression of diet-induced steatohepatitis. This evidence concerns the gene PPARA and metabolic dysfunction-associated steatohepatitis.