Metabolic dysfunctionâassociated steatohepatitisâdriven hepatocellular carcinoma (MASHâHCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factorâalpha (TNFâα) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNFâα converting enzyme (TACE) inhibition as a promising targeted therapy against AATFâmediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASHâHCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2âÎŒL·gâ1, weekly) for 24âweeks. TACE activity, TNFâα levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12âweeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12âweeks and advanced fibrosis with HCC at 24âweeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNFâα, which upregulated AATF, a key molecular driver of MASHâHCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATFâmediated inflammation, fibrosis, and oncogenesis in MASHâHCC, offering a potential target for therapeutic intervention.