Histone demethylases regulate ferroptosis in metabolic dysfunction-associated steatotic liver disease via epigenetic modification.

Ferroptosis, an iron-dependent, non-apoptotic form of cell death, is characterised by pathogenic lipid reactive oxygen species accumulation, dysregulated iron homeostasis, and oxidative stress-induced membrane damage. Numerous studies have demonstrated that ferroptosis plays a critical role in the pathogenesis of metabolic disorders and related cancers, particularly metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma. Epigenetic modifications, notably aberrant expression of histone lysine demethylases (KDMs), have been strongly associated with both ferroptosis and MASLD. This review systematically summarises how KDM family members regulate ferroptosis-related gene transcription through epigenetic mechanisms, along with their specific roles in MASLD progression. Additionally, current progress and challenges in the potential application of KDM inhibitors in regulating ferroptosis and MASLD treatment are discussed, with the aim of providing a scientific foundation for the translational development of therapeutic strategies.