Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver injuries, including steatosis to steatohepatitis (MASH), liver fibrosis, cirrhosis, and relevant complications. The liver mainly comprises hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), immune cells (T cells, B cells), and hepatic stellate cells (HSCs). Crosstalk among these different liver cells, endogenous aberrant glycolipid metabolism, and altered gut dysbiosis are involved in the pathophysiology of MASLD. This review systematically examines advances in understanding the molecular pathogenesis of MASLD, with a focus on emerging therapeutic targets and translational clinical trials. We first delineate the crucial regulatory mechanisms involving diverse liver cells and the gut-liver axis in MASLD development. These cell-specific pathogenic insights offer valuable perspectives for advancing precision medicine approaches in MASLD treatment. Furthermore, we evaluate potential therapeutic targets and summarize clinical trials currently underway. By comprehensively updating the MASLD pathophysiology and identifying promising strategies, this review aims to facilitate the development of novel pharmacotherapies for this increasingly prevalent condition.
Humans ; Fatty Liver/therapy* ; Animals ; Liver/pathology* ; Kupffer Cells/metabolism* ; Hepatocytes/metabolism* ; Hepatic Stellate Cells/metabolism*

The portal vein system is the main blood supply system of the liver, and damage to the portal vein system caused by cirrhotic portal hypertension may be the second hit to the liver. Protection of the portal vein will ensure sufficient blood supply of the liver and maintain its structure and function. Starting from the physiological structure and pathological changes of the portal vein, this article elaborates on the adverse effect of portal hypertension on the liver from the three new perspectives of thrombosis of the portal system, abnormal angiogenesis, and disturbance of hepatic sinusoidal homeostasis. It is suggested to change the current status of passive treatment of portal hypertension complications and encourage scientific exploration to reduce portal hypertension from multiple angles as early as possible to avoid repeated endoscopic devascularization of collateral circulation and splenectomy, so as to reduce various factors for the damage of the portal system, maintain the homeostasis of the portal system, and protect the liver.

The incidence rate of nonalcoholic steatohepatitis is gradually increasing year by year, which calls for an urgent need for effective therapeutic drugs. In recent years, various drugs have been developed, including anti-oxidative stress drugs, insulin sensitizers, PPAR agonists, thyroid receptor agonists, farnesoid X receptor agonists, ASK1 inhibitors, and pan-caspase inhibitors. This article reviews the clinical studies on the therapeutic drugs for nonalcoholic steatohepatitis and summarizes the efficacy and safety of each drug, in order to provide a reference for clinical practice.