TACE inhibition: a promising therapeutic intervention against AATF‐mediated steatohepatitis to hepatocarcinogenesis

Abstract

Metabolic dysfunction‐associated steatohepatitis‐driven hepatocellular carcinoma (MASH‐HCC) 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 factor‐alpha (TNF‐α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF‐α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF‐mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH‐HCC 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; 0.2 μL·g−1, weekly) for 24 weeks. TACE activity, TNF‐α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, 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 12 weeks and advanced fibrosis with HCC at 24 weeks. 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 TNF‐α, which upregulated AATF, a key molecular driver of MASH‐HCC. 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 AATF‐mediated inflammation, fibrosis, and oncogenesis in MASH‐HCC, offering a potential target for therapeutic intervention.

Green Jackfruit Flour Prevents Metabolic Dysfunction-Associated Steatohepatitis and Progression to Hepatocellular Carcinoma via the AMPK and MAPK Signaling Pathways

“…Of note, green jackfruit flour differs significantly from the placebo in its dietary fiber composition [20] and it is also evident that unripe jackfruit has a higher fiber content when compared to ripe jackfruit [45]. Dietary fibers, encompassing a variety of plant-derived carbohydrates resistant to digestion by human enzymes, play a pivotal role in MASLD management [46].…”

Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

“…Further studies revealed the role of AATF in impeding HCC angiogenesis by downregulating PEDF (24). Recently, we investigated the role of AATF in MASH-HCC and showed that TACE inhibition by Marimastat prevents AATF-mediated inflammation, fibrosis, and oncogenesis (27). In the current study, we identified for the first time the role of AATF in lipid metabolism and its implications in the development of MASH.…”

“…Studies have also demonstrated the inhibitory effects of curcumin on MASH-HCC by downregulating AATF via the KLF4-SP1 pathway (26). We recently explored the involvement of the SIRT1-TIMP3-TACE axis in AATF upregulation, with subsequent TACE inhibition leading to AATF downregulation and attenuation of MASH-associated liver tumorigenesis (27). However, the mechanistic role of AATF in the pathophysiology of MASH remains poorly understood.…”