Ferroptosis in MASLD: From molecular mechanisms to therapeutic opportunities

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver conditions, ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and cirrhosis. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathogenic mechanism in MASLD. Given the liver's pivotal role in iron and lipid metabolism, hepatocytes are highly susceptible to ferroptotic injury, which amplifies hepatic oxidative stress, inflammation, and fibrogenesis. Beyond the liver, ferroptosis has also been linked to systemic metabolic dysfunction and extrahepatic organ involvement in MASLD. This review summarizes the molecular pathways linking ferroptosis to disease progression across the MASLD spectrum, integrating evidence from preclinical and clinical studies. We further discuss emerging biomarkers and the therapeutic strategies targeting ferroptosis, including iron chelation, antioxidants, and lipid peroxidation inhibitors. Understanding how metabolic stress and ferroptotic signaling interact may open new avenues for treating MASLD and its systemic complications.

Keywords: biomarkers; ferroptosis; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; multisystem disease; therapeutic targeting; translation to patients.