Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and then more severe complications occur. Recently, ellagic acid (EA) has drawn attention mainly due to its biological functionalities and a series of molecular targets. However, the molecular mechanism by which EA attenuates hepatic steatosis in individuals with undesirable hepatic genetic alterations remains rarely studied. Here, we evaluate the therapeutic efficacy of EA in a hepatic steatosis mouse model featuring elevated expression of sterol regulatory element-binding protein-1 (SREBP-1) and its downstream modulators of lipogenesis by hydrodynamic injection of v-akt murine thymoma viral oncogene homolog (AKT). Hematoxylin and eosin staining, oil red O staining, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction (qPCR) were performed for mechanistic investigations. Human hepatoma cell lines were used for mechanical validation in vitro. The results suggest that EA lightens the accumulation of lipids in hepatocytes of AKT-injected mice and an oleic acid-induced in vitro hepatic steatosis model. Mechanistically, EA administration decreases the expression of phospho-AKT (Thr308) and suppresses two effectors lying downstream of the AKT/mTORC1 pathway, ribosomal protein S6 (RPS6) and SREBP-1, in the AKT-injected mice. The consequence of the EA-mediated decrease of SREBP-1 is found to be a transcriptional and translational inhibition of fatty acid synthase (FASN), accompanied by the downregulation of acetyl-CoA carboxylase (ACC). Consistent with in vivo findings, EA efficiently represses the SREBP-1/FASN axis in vitro. Collectively, our study provides a novel mechanism whereby EA alleviates AKT-triggered hepatic de novo lipogenesis, indicating that EA might serve as a potential agent in the therapy of hepatic steatosis in patients with NAFLD and/or steatosis-associated complications, especially in that characterized by activation of AKT/mTORC1 signaling in the liver.

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.

Objective: The objective of this study was to enhance the solubility and bioavailability of Lupeol. Methods: Utilizing a thin-film dispersion method, we prepared Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes, which was characterized by SEM, mean diameter, PDI, zeta potential and entrapment efficiency(EE). The EE, in vitro release and stability of Lupeol-loaded PEGylated liposomes, were detected by HPLC. In addition to the safety evaluation, the evaluation was carried out on HepG2 cells in vitro; the pharmacokinetics were carried out after i.v. in the rats. Results: The size, PDI, zeta potential, and EE of Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes were 126.9 nm, 0.246, -1.97 mV, 87%; 97.23 nm, 0.25, 1.6 mV, 86.2%, respectively. Lupeol-loaded PEGylated liposomes showed the slow-release effect in vitro release experiments. Lupeol-loaded PEGylated liposomes offered significant advantages over other experimental groups in vitro studies, such as the highest inhibition rate and the highest apoptosis rate. We also found that Lupeol-loaded PEGylated liposomes blocked cells in the G₂M phase. The pharmacokinetics result showed that the AUC of Lupeol-loaded PEGylated liposomes group was 3.2 times higher than free Lupeol group after i.v., the MRT and t_1/2 values of Lupeol-loaded PEGylated liposomes (MRT =6.09 h, t_1/2 =12.94 h) showed improvements of 2.5 and 4.1 times compared to free Lupeol (MRT= 2.43 h, t_1/2= 3.16 h) . Conclusion: The Lupeol-loaded PEGylated liposomes have successfully solved its poor hydrophilicity, low bioavailability.

Nanomaterial-based cancer therapy faces significant limitations due to the complex nature of the tumor microenvironment (TME). Starvation therapy is an emerging therapeutic approach that targets tumor cell metabolism using glucose oxidase (GOx). Importantly, it can provide a material or environmental foundation for other diverse therapeutic methods by manipulating the properties of the TME, such as acidity, hydrogen peroxide (H₂O₂) levels, and hypoxia degree. In recent years, this cascade strategy has been extensively applied in nanoplatforms for ongoing synergetic therapy and still holds undeniable potential. However, only a few review articles comprehensively elucidate the rational designs of nanoplatforms for synergetic therapeutic regimens revolving around the conception of the cascade strategy. Therefore, this review focuses on innovative cascade strategies for GOx-based synergetic therapy from representative paradigms to state-of-the-art reports to provide an instructive, comprehensive, and insightful reference for readers. Thereafter, we discuss the remaining challenges and offer a critical perspective on the further advancement of GOx-facilitated cancer treatment toward clinical translation.