TDP-43 post-transcriptionally regulates SLC7A7 to promote ferroptosis and metabolic dysfunction-associated steatohepatitis upon arsenic exposure.

Chronic exposure to sodium arsenite (NaAsO2) is a recognized environmental driver of metabolic dysfunction-associated steatohepatitis (MASH), yet the post-transcriptional regulatory mechanisms underlying this hepatotoxicity remain poorly understood. Here, we identify a novel pathway involving the RNA-binding protein TDP-43 in arsenic-induced hepatotoxicity. In both in vivo and in vitro models, arsenic exposure triggered significant nuclear retention of TDP-43. Importantly, beyond its canonical nuclear localization, we found that this retention confers a hepatocyte-specific function that mediates the toxic response to arsenic. Mechanistically, RNA immunoprecipitation (RIP) and functional analyses revealed that nuclear TDP-43 directly binds to the mRNA of solute carrier family 7 member 7 (SLC7A7). This interaction post-transcriptionally stabilizes SLC7A7 transcripts, leading to the aberrant accumulation of this cationic amino acid transporter. Functionally, SLC7A7 overexpression depleted intracellular glutathione (GSH), thereby sensitizing hepatocytes to lipid peroxidation and ferroptosis. Notably, silencing either TDP-43 or SLC7A7 effectively ameliorated arsenic-induced hepatic inflammation and ferroptotic injury, whereas SLC7A7 overexpression abolished the protective effects of TDP-43 depletion. Collectively, these findings delineate a crucial TDP-43/SLC7A7/Ferroptosis axis in arsenic-induced liver injury, highlighting a post-transcriptional regulatory function of TDP-43 in mediating environmental metabolic toxicity.