Apoptosis antagonizing transcription factor‐mediated liver damage and inflammation to cancer: Therapeutic intervention by curcumin in experimental metabolic dysfunction associated steatohepatitis‐hepatocellular carcinoma

Abstract

In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)‐ driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF‐mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH‐HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4‐ 0.2 μL/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel‐like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein‐1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4‐Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH‐HCC in humans.

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

“…Tissues were scored blindfolded for the degree of steatosis, hepatocyte ballooning, and lobular inflammation by an expert pathologist at JSS Hospital. MASLD activity scoring was calculated using these scores according to the FLIP algorithm and NASH-clinical research network (CRN) criteria [24,25].…”

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

“…Our previous investigations have revealed elevated levels of hepatic AATF in HCC, where it plays a significant role in promoting tumor angiogenesis (25). 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).…”