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Thioredoxin-interacting Protein Targets PRDX3 to Induce Mitochondria-associated Ferroptosis and Promote MASLD

ABSTRACT: Hepatocyte ferroptosis has emerged as a pivotal driver of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the mechanisms coupling metabolic stress to the ferroptotic machinery remain elusive. Here, we identify thioredoxin-interacting protein (TXNIP) as a requisite mediator of mitochondria-associated ferroptosis during MASLD progression. Interrogation of clinical datasets and experimental models revealed that hepatic TXNIP is robustly upregulated in MASH patients, positively correlated with disease severity and pro-ferroptotic gene signatures. Txnip-deficient mice conferred significant protection against high-fat diet-induced steatohepatitis and hepatic ferroptosis. Mechanistically, metabolic stress triggers the mitochondrial translocation of TXNIP, where it directly interacts with the mitochondrial-specific peroxidase Peroxiredoxin 3 (PRDX3). This physical association suppresses PRDX3 antioxidant activity, leading to mitochondrial reactive oxygen species (ROS) accumulation, iron overload, and lipid peroxidation. Functional rescue experiments confirmed that PRDX3 overexpression effectively abrogates TXNIP-induced ferroptosis, whereas PRDX3 silencing exacerbates the ferroptotic phenotype in TXNIP-overexpressing cells. Collectively, these findings establish the TXNIP-PRDX3 axis as a critical regulatory hub for mitochondrial redox homeostasis and identify this interaction as a potential therapeutic vulnerability to arrest MASLD progression.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wentin Zhang

PROVIDER: PXD074828 | iProX | Sun Feb 15 00:00:00 GMT 2026

REPOSITORIES: iProX

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