Abstract
Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patients with MASLD,we found high expression levels of SLC7A11 that were correlated directly with clinical grade.Using both loss-of-function and gain-of-function genetic models,we found that Slc7al 1 deficiency accelerated MASLD progression via classic cystine/cysteine deficiency-induced ferroptosis,while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11.Consistent with these findings,we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD,and the serum serine/glutamate ratio was significantly lower in these pre-clinical disease models,suggesting that it might serve as a prognostic biomarker for MASLD in patients.These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.
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