Ebastine-mediated destabilization of E3 ligase MKRN1 protects against metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition encompassing metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). The heterogeneous and complex nature of MASLD complicates optimal drug development. Ebastine, an antihistamine, exhibits antitumor activity in various types of cancer. However, its effects on MASH remain unexplored. In the present study, we identified ebastine as a potential treatment for MASH. Our results indicated that ebastine acts as a novel MKRN1 inhibitor by promoting MKRN1 destabilization through self-ubiquitination, leading to AMP-activated protein kinase (AMPK) activation. Ebastine appeared to bind to the C-terminal domain of MKRN1, particularly at residues R298 and K360. Notably, Mkrn1 knockout (KO) mice demonstrated resistance to MASH, including obesity, steatosis, inflammation, and fibrosis under high-fat-high-fructose diet (HFHFD) conditions. Additionally, liver-specific Mkrn1 knockdown using AAV8 alleviated MASH symptoms in HFHFD-fed mice, implicating MKRN1 as a potential therapeutic target. Consistent with these findings, treatment with ebastine significantly reduced the risk of MASH in HFHFD-fed mice, with a decrease in MKRN1 expression and an increase in AMPK activity. Our study suggests that ebastine binds to MKRN1, promoting its destabilization and subsequent degradation by stimulating its ubiquitination. This enhances AMPK stability and activity, suppressing lipid accumulation, inflammation, and fibrosis. Moreover, the knockout of Mkrn1 mice decreased the risk of MASH, suggesting that ebastine could be a promising therapeutic agent for the treatment of MASH.

Kim S ，Han HJ ，Rho H ，Kang S ，Mukherjee S ，Kim J ，Kim D ，Ko HW ，Lim SM ，Im SS ，Chung JY ，Song J ... -  《-》

Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating aryl hydrocarbon receptor-dependent AMPK signaling.

Patil NY ，Rus I ，Ampadu F ，Abu Shukair HM ，Bonvicino S ，Brush RS ，Eaton E ，Agbaga MP ，Oh TG ，Friedman JE ，Joshi AD ... -  《-》

Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation.

Lee MS ，Han HJ ，Han SY ，Kim IY ，Chae S ，Lee CS ，Kim SE ，Yoon SG ，Park JW ，Kim JH ，Shin S ，Jeong M ，Ko A ，Lee HY ，Oh KJ ，Lee YH ，Bae KH ，Koo SH ，Kim JW ，Seong JK ，Hwang D ，Song J ... -  《Nature Communications》

Polyoxometalates Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease by Activating the AMPK Signaling Pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disorder, has garnered increasing attention globally owing to its associated health complications. However, the lack of available therapeutic medications and inadequate management of complications in metabolic dysfunction-associated steatohepatitis (MASH) present significant challenges. There are little studies evaluating the effectiveness of POM in treating MASLD. In this study, we synthesized polyoxometalates (POM) for potential treatment of MASLD. We induced liver disease in mice using two approaches: feeding a high-fat diet (HFD) to establish MASLD or feeding a methionine-choline deficient (MCD) diet to induce hepatic lipotoxicity and MASH. Various metabolic parameters were detected, and biochemical and histological evaluations were conducted on MASLD. Western blotting, qRT-PCR and immunofluorescence assays were used to elucidate the molecular mechanism of POM in the treatment of MASLD. POM therapy resulted in significant improvements in weight gain, dyslipidemia, liver injury, and hepatic steatosis in mice fed a HFD. Notably, in a more severe dietary-induced MASH model with MCD diet, POM significantly attenuated hepatic lipid accumulation, inflammation, and fibrosis. POM treatment effectively attenuated palmitic acid and oleic acid-induced lipid accumulation in HepG2 and Huh7 cells by targeting the AMPK pathway to regulate lipid metabolism, which was confirmed by AMPK inhibitor. Additionally, the activation of AMPK signaling by POM suppressed the expression of lipid synthesis genes, including sterol regulatory element-binding protein 1c (SREBP1c) and SREBP2, while concurrently upregulating the expression of sirtuin 1 (SIRT1) to promote fatty acid oxidation. These findings suggest that POM is a promising therapeutic strategy with high efficacy in multiple MASLD models.

Wang D ，Wang J ，Yin Z ，Gong K ，Zhang S ，Zha Z ，Duan Y ... -  《International Journal of Nanomedicine》

Green jackfruit flour ameliorates MASH and development of HCC via the AMPK and MAPK signaling pathways in experimental model systems.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious public health concern. Given the paucity of approved therapeutic strategies for this lifestyle disorder, dietary interventions may prove effective. We evaluated the mechanisms of how green jackfruit flour (JF) ameliorates metabolic-dysfunction-associated steatohepatitis (MASH) and halts the progression to hepatocellular carcinoma (HCC). The study used murine models of MASH and MASH-HCC that closely mimic human MASLD. C57Bl/6 male mice were fed with chow or western diet with normal or sugar water for 12 weeks, then randomized to receive either 5 kcal% green jackfruit flour (JF) or an equal volume of placebo flour (PB). JF significantly reduced body weight, liver injury, and insulin resistance, and alleviated obesity, steatosis, inflammation, fibrosis, and tumor development in WDSW or WDSW/CCl4 mice compared to placebo. Furthermore, JF activated AMPK (AMP-activated protein kinase) and inhibited MAPK (mitogen-activated protein kinase) signaling pathways in MASH and MASH-HCC models, respectively. Sodium propionate treatment, the primary short-chain fatty acid entering the liver from JF's soluble fiber microbial fermentation, further supported these mechanistic insights. Hence, our findings present strong evidence of JF's therapeutic potential in attenuating MASH and MASH-HCC, warranting further investigation of JF's efficacy as a dietary intervention in clinical trials.

Suresh D ，Gunaseelan B ，Srinivas AN ，Bharadwaj A ，Joseph J ，Megha ，Varughese T ，Satish S ，Suvarna D ，Santhekadur PK ，Chidambaram SB ，Duseja A ，Kumar DP ... -  《Scientific Reports》