Ferroptosis may link gut microbiota dysbiosis to the progression of metabolic dysfunction associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), affects a substantial proportion of the global adult population and is a leading cause of chronic liver disease. Its progression reflects interactions among metabolic dysfunction, genetic susceptibility, diet, inflammation, and gut-liver axis disruption. This narrative review examines the emerging evidence supporting ferroptosis, an iron-dependent form of regulated cell death characterised by lethal lipid peroxidation, as a potential mechanistic link between gut microbiota dysbiosis and MASLD progression. Dysbiosis in MASLD has been associated with reduced microbial diversity, altered microbial profiles, impaired intestinal barrier integrity, and increased exposure to gut-derived inflammatory products such as lipopolysaccharide. In parallel, ferroptosis-related pathways involving glutathione peroxidase 4, system Xc⁻, nuclear factor erythroid 2-related factor 2, acyl-CoA synthetase long-chain family member 4, iron handling, and lipid peroxide detoxification have been implicated in hepatic injury. Preclinical studies suggest dysbiosis-associated inflammation, altered bile acid signalling, short-chain fatty acid depletion, and disturbed iron homeostasis may create a hepatic environment permissive for ferrotopic injury. Human studies remain largely associative, linking dysbiosis signatures, altered microbial metabolites, iron indices, oxidative stress markers, and disease severity without establishing direct causality. The proposed dysbiosis-ferroptosis axis may inform future biomarker development and therapeutic research, but candidate markers such as malondialdehyde, 4-hydroxynonenal, ferritin, and MRI-based iron measures are not specific for ferroptosis, and ferroptosis-targeted therapies remain investigational in MASLD. This review synthesises current evidence, identifies stronger and weaker support, and outlines research priorities needed to clarify whether gut-derived signals directly modulate ferroptotic liver injury in human MASLD.