NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway

NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity.

• Impaired autophagy is linked to metabolic dysfunction-associated steatotic liver disease (MASLD).
• Hepatic NSD2 deficiency improved diet-induced autophagy impairment and reduced fat accumulation in the liver.
• Overexpression of NSD2 worsened autophagy impairment and increased fat accumulation.
• NSD2 epigenetically suppresses a protein called TFEB, which is important for autophagy, by modifying histones.
• Inhibition of NSD2 in human liver organoids reduced fat accumulation, suggesting a potential therapeutic approach.

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