Kyoung Ah Min

Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from the convergence of hepatic lipid overload, insulin resistance, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation, yet effective pharmacotherapy remains limited. Increasingly, adipose tissue is recognized not as a passive lipid depot but as an endocrine organ whose secreted adipokines regulate hepatic lipid and glucose metabolism, inflammatory signaling, and fibrogenesis through pathways including AMP-activated protein kinase (AMPK), peroxisome proliferator–activated receptor-α (PPARα), protein kinase B (Akt), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Restoring adipokine activity can reduce hepatic triglyceride levels, enhance fatty acid β-oxidation, improve insulin sensitivity, and attenuate fibrotic remodeling, but the translational maturity of individual targets varies considerably. Among these, only the fibroblast growth factor 21 (FGF21) programme can currently be described as clinically advanced, having reached Phase 2b/3 human trials; adiponectin remains the most mechanistically characterized hepatoprotective adipokine, but adiponectin-directed agents (adiponectin receptor (AdipoR) agonists, adiponectin mimetics) are still preclinical. Two interlocking barriers separate this biological rationale from durable therapeutic application: adipokine resistance, which appears to be a systemic feature of advanced disease that blunts signaling across multiple axes, and the short plasma half-lives and proteolytic susceptibility of native adipokines. This review examines the molecular mechanisms, pharmacokinetics, and receptor-sensitization strategies relevant to adipokine-based therapy, including PEGylation, glycoPEGylation, fragment crystallizable (Fc)-fusion, and rational combination regimens, positioning adipokine-targeted therapy as an attractive approach to MASLD treatment.

Metabolic-associated steatotic liver disease (MASLD) affects an estimated 25–30% of the global adult population and represents a leading cause of liver-related morbidity. However, approved pharmacological therapies remain strictly limited. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine/threonine kinase and major regulator of cellular energy homeostasis, is chronically suppressed in the steatotic liver through hyperinsulinemia, ceramide signaling, oxidative stress, and epigenetic silencing of its upstream activator LKB1. This suppression removes a critical brake on de novo lipogenesis while simultaneously impairing fatty acid β-oxidation, mitochondrial quality control, anti-inflammatory signaling, and hepatic stellate cell quiescence. Thus, AMPK restoration may serve as an effective strategy capable of addressing multiple pathological drivers of MASLD. This review examines the molecular architecture of the AMPK heterotrimer, the downstream signaling networks governing hepatic lipid metabolism, glucose homeostasis, and fibrogenesis, and a spectrum of AMPK-activating pharmacology relevant to MASLD. Furthermore, it would introduce indirect activators including metformin, berberine, resveratrol, and related phytochemicals, as well as direct allosteric activators targeting the ADaM site, such as A-769662, PF-06409577, MK-8722, Compound 991, and the clinical-stage compound O304. Translational challenges confronting this therapeutic class are critically evaluated.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are a growing global health burden with extremely limited pharmacological options, thereby indicating an urgent need for innovative therapeutic strategies. Hepatokines are liver-derived secreted proteins that coordinate metabolic communication between the liver and peripheral organs and have emerged as mechanistically compelling therapeutic candidates. This review comprehensively examines beneficial hepatokines with protective roles in MASLD/MASH, detailing their molecular mechanisms of action across key metabolic tissues, including their effects on hepatic lipid metabolism, insulin sensitivity, inflammatory signaling, and fibrogenesis. We further discuss the fundamental pharmacokinetic barriers of these protein therapeutics, particularly their susceptibility to renal clearance and proteolytic degradation. Furthermore, we examine the principal half-life extension strategies to overcome these limitations, with particular emphasis on their clinical application to FGF21-based drug candidates that are currently advancing through phase 3 trials. Overall, this review highlights the therapeutic potential of hepatokine-based biologics and the critical role of protein engineering in translating these mechanistic insights into durable, clinically viable treatments for MASLD/MASH.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is now the most common chronic liver disorder worldwide. Once started with hepatic steatosis, it can progress to metabolic dysfunction–associated steaohepatitis (MASH), cirrhosis, and even hepatocellular carcinoma. Insulin resistance is a major driver of hepatic lipogenesis in this disease context. Gut barrier dysfunction also contributes to the progression to MASH by allowing bacterial lipopolysaccharide (LPS) to breach into the hepatic tissues. Amphibian skin secretion peptides (ASSPs) are therefore of particular interest, given their combined metabolic and antimicrobial activities. Some ASSPs enhance glucose-stimulated insulin secretion and GLP-1 release, whereas others attenuate LPS-driven inflammatory signaling. This review introduces these ASSPs with a focus on their insulinotropic/incretinotropic and immunomodulatory activities. Also, in the latter part, pharmaceutical strategies to improve blood circulation time and structural stability would be discussed.

Three medium-chain fatty acids (MCFAs), namely decanoic acid, octanoic acid, and hexanoic acid, were identified in ozonated sunflower oil (OSO) using high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC/MS). All three MCFAs exhibited strong in vitro antioxidant activity to enhance high-density lipoprotein (HDL)-associated paraoxonase and protected low-density lipoproteins (LDL) from oxidative damage caused by Cu²⁺ ions. Consistently, MCFAs displayed substantial cellular antioxidant activity and minimized carboxymethyllysine (CML)-induced reactive oxygen species (ROS) generation and apoptotic cell death in zebrafish embryos. In adult zebrafish, MCFAs treatment mitigated CML-induced acute death and swimming abnormalities, and substantially augmented plasma sulfhydryl content, ferric ion reduction ability (FRA), and paraoxonase (PON)-like activity. Also, MCFA-treated zebrafish showed lower blood glucose, total cholesterol (TC) and triglycerides (TG) with raising HDL cholesterol levels. The MCFAs showed substantial inhibition of hepatic ROS generation, neutrophil efflux, interleukin (IL)-6 production, and steatosis, leading to hepatoprotection against CML-triggered adversity. Consistent with hepatic histology results, reduced plasma hepatic function biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in MCFA-treated groups than in the CML-treated group. In the kidney, MCFA treatment effectively reduced oxidative stress and cellular senescence and protected against kidney damage induced by exposure to CML. The study concludes the presence of three MCFAs in the OSO, which serve as functional antioxidants and anti-inflammatory agents, accounting for its diverse pharmacological properties.

Introduction: Extensive research has focused on identifying effective treatments for NAFLD, with numerous bioactive peptide candidates showing significant promise. In this research, a long-acting esculentin-2CHa(1-30)-coated AuNPs (ESC-ABD-AuNPs) was developed and the applicability was evaluated for their use in the treatment of non-alcoholic fatty liver disease (NAFLD). Methods: ESC-ABD-AuNPs were synthesized by adopting a 1-step reduction process and the successful preparation of the nanoparticles (NPs) was assessed by various physical characterizations including transmission electron microscopy (TEM), ultraviolet-visible (UV-VIS) absorption spectra, dynamic light scattering (DLS), and Fourier Transform Infrared Spectroscopy (FT-IR). After the ESC-ABD-AuNPs were prepared, cytotoxicity, pharmacokinetics (PK), and biodistribution profiles were identified. Then, with a high-fat diet (HFD)-fed obese mice model, efficacy studies were carried out focused on their effects for anti-hyperglycemia and anti-NAFLD. Furthermore, the feasibility of loading a small molecule onto the NPs was evaluated for potential combination therapy. Results: ESC-ABD-AuNPs were synthesized with an average hydrodynamic size of 120 (± 10) nm and demonstrated good stability and an extended plasma half-life of 28.3 h. The NPs exhibited high liver accumulation and were well tolerated in cell viability tests. In PK and biodistribution studies, ESC-ABD-AuNPs showed prolonged retention in major organs, such as the pancreas and the liver. Therapeutic efficacy was demonstrated in the HFD-fed obese mice, where the ESC-ABD-AuNPs significantly reduced blood glucose levels, improved glucose tolerance, and mitigated liver fat accumulation. The ESC-ABD-AuNPs platform also showed potential for combination therapies, demonstrated by its ability to load obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, found effective for the treatment of NAFLD in clinical studies. Conclusion: Overall, this study has demonstrated the promising potential of ESC-ABD-AuNPs as a novel treatment for NAFLD. This research suggests that ESC-ABD-AuNPs could be a significant advancement in drug delivery and liver disease treatment, particularly for combination therapies.

Background: Gold nanoparticles (NPs) have drawn great attention in the area of biomedical research with their relatively safe and versatile properties. This study aimed to synthesize long-lasting exendin-4-coated gold NPs (EX-ABD-AFF-GoldNPs) and evaluate their anti-diabetic effects in vivo. Methods: In the present study, EX-ABD-AFF-GoldNPs were synthesized using a simple one-step aqueous reduction method. The physical characterization of the prepared particles verified the successful formation of the EX-ABD-AFF-GoldNPs through dynamic light scattering (DLS), transmission electron microscopy (TEM), ultraviolet–visible (UV-VIS) light spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The anti-hyperglycemic and anti-obesity effects were assessed in high-fat diet (HFD)-fed obese diabetic mice. Additionally, pharmacokinetics (PK) and biodistribution studies were performed to verify the long-lasting properties. Results: The EX-ABD-AFF-GoldNPs were conglomerates of smaller globular-shaped particles, and the average size was 110(±14) nm, based on the TEM images. Safety assessments using Min6, HepG2, and B16F10 cell lines demonstrated low cytotoxicity, with over 80% cell viability up to the highest tested concentration of 150 μg/mL (as EX-ABD-AFF). Notably, the animal studies showed that the EX-ABD-AFF-GoldNPs exhibited significant hypoglycemic activity, comparable to the EX-ABD-AFF, in the HFD-fed mice. A 4-week treatment with EX-ABD-AFF-GoldNPs produced similar reductions in blood glucose and body weight to the EX-ABD-AFF, without any apparent toxicity. Furthermore, the PK and biodistribution study results confirmed the long-lasting properties (plasma half-life: 43.6 h) of the particles. Conclusions: Overall, this study demonstrated that the preparation of therapeutic protein-loaded gold NPs is feasible and, despite their much larger size compared with the protein, EX-ABD-AFF-GoldNPs can be successfully absorbed through the subcutaneous route and show nearly equivalent hypoglycemic activity to the EX-ABD-AFF protein. Finally, this study showed that long-lasting properties could be acquired by only coating EX-ABD-AFF onto gold NPs.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal^® SR 200 mg capsules have higher drug release rates than Cilostan^® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC_0-t, and AUC_0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal^® SR 200 mg capsules compared with Cilostan^® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal^® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan^® CR 200 mg tablets.