Grape-Derived Exosome-like Nanoparticles Ameliorate Prediabetes in Mice via Amino Acid Metabolic Reprogramming.

In June 2023, aiming to more accurately reflect the underlying lipid metabolic issues, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) reached a consensus to reclassify nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) (). MASLD is a chronic liver disease. Its diagnosis requires that liver steatosis should involve more than 5% of liver cells, and at the same time, it should be accompanied by at least one metabolic risk factor (; ), such as obesity, type 2 diabetes, hypertension, dyslipidemia or insulin resistance (IR). The occurrence and development of this disease are jointly influenced by multiple factors including lifestyle, dietary habits, drug exposure and genetic susceptibility. The increasing prevalence of metabolic risk factors is the main cause driving the continuous increase in the disease burden. Currently, about 30%–40% of adults worldwide suffer from this disease, highlighting its status as a significant public health challenge (). If no effective intervention is taken, its health impact will become increasingly severe. The disease can progress to MASH, presenting with liver cell damage, inflammation and fibrosis, and eventually may develop into liver cirrhosis and hepatocellular carcinoma (HCC), even requiring liver transplantation (). In recent years, there has been significant advancement in pharmacological studies on MASLD, with therapeutic approaches shifting from traditional lifestyle adjustments to precision-targeted treatments and combination therapies that target various pathophysiological pathways. However, current therapeutic approaches still face certain drawbacks, underscoring the need for a more integrated understanding of systemic pathogenic mechanisms. While many reviews have elaborated on the potential of natural products, including flavonoids, phenolic acids, and alkaloids, in treating MASLD, there remain three key drawbacks that need addressing. To start with, most current research tends to offer one-sided accounts that center on individual drug actions, such as improving lipid buildup, lowering inflammatory factors, or lessening oxidative stress. Consequently, they rarely adopt the multiple-hit hypothesis as a cohesive framework to systematically explore the causal links between these pathological events. Second, the regulatory mechanisms of protein post-translational modifications (PTMs) and the roles of diverse cell death pathways are not systematically elucidated, with most analyses confined to phenomenological descriptions. Additionally, the systematic exploration of how natural alkaloids interact with key regulatory factors in these pathways remains limited, hindering a comprehensive understanding of their therapeutic potential, and there is a notable lack of comparative studies between natural products and recently Food and Drug Administration (FDA)-approved drugs. This gap overlooks the possible clinical significance of natural alkaloids as supplementary or substitute treatment approaches.