Pirfenidone as a Pleiotropic Antifibrotic Agent in Metabolic Steatohepatitis: From Mechanisms to Clinical Evidence.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive phenotype of steatotic liver disease that can lead to advanced fibrosis, cirrhosis and liver-related complications. Pirfenidone is a small synthetic molecule that was originally approved for idiopathic pulmonary fibrosis. It has pleiotropic antifibrotic, anti-inflammatory, antioxidant, and immunomodulatory properties. In preclinical liver models, pirfenidone reduces hepatic stellate cell activation, collagen deposition, oxidative stress and proinflammatory cytokine expression, largely through the modulation of transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), mitogen-activated protein kinases, and the Nrf2 axis. Early clinical trials, including the large prospective cohort PROMETEO, the randomized controlled trial in compensated cirrhosis ODISEA, and the translational trial in post-sustained viral response fibrosis MINERVA, show improvements in noninvasive fibrosis markers, liver function tests, quality of life, and parallel epigenetic remodeling. These data suggest that pirfenidone acts on central fibrogenic biology and may contribute to histological regression in advanced disease. Larger and longer trials, as well as rational combinations with metabolic agents, are needed to define its therapeutic role in MASH.