Therapeutic Targets and Approaches to Manage Inflammation of NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.

Keywords: NAFLD; NASH; inflammation; pathophysiology; therapy.

Figure 1

Non-alcoholic fatty liver disease (NAFLD) as an important driving force of multisystemic disorders. NAFLD is a critical contributor to multisystemic disorders. It progresses from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, significantly impacting liver health. Metabolic abnormalities such as obesity, hyperglycemia, hypertension, and hyperlipidemia closely interact with NAFLD. Additionally, NAFLD is linked to systemic complications, including cardiovascular disease, type 2 diabetes, chronic kidney disease, obstructive sleep apnea, and osteoporosis, emphasizing its role as a multifaceted metabolic condition. (Created in https://BioRender.com).

Figure 2

Drug targets for the treatment of NAFLD/NASH. This figure illustrates key drug targets and mechanisms for the treatment of NAFLD/NASH. It highlights the pathways involved in metabolic regulation, anti-inflammatory strategies, bile acid metabolism modulation, and antifibrotic approaches. These targets address critical pathological processes, including metabolic dysregulation, inflammation, and liver fibrosis, providing a framework for precision therapy in NAFLD/NASH. (Created in https://BioRender.com). Black words indicate the pathway or molecules acting on that pathway; The red and blue words contain the names of drug targets. The red words and lines together indicate that the drug target activates the pathway, while the blue words and lines together indicate that the drug target exerts an inhibitory effect.

Figure 3

Triggers of the inflammation in NAFLD. Triggers of inflammation in NAFLD involve complex interactions among metabolic, cellular, and microbial factors that drive liver injury and disease progression. Adipocyte death releases cytokines, lipotoxic substances, and free fatty acids, worsening liver injury and fibrosis, while hepatocyte death activates inflammatory pathways and fibrosis via DAMPs. Gut microbiota dysbiosis disrupts the gut–liver axis, allowing endotoxins like LPS to trigger hepatic inflammation through Toll-like receptors. High-fructose and high-fat diets exacerbate oxidative stress, lipotoxicity, and mitochondrial dysfunction, intensifying liver inflammation and metabolic imbalance. (Created in https://BioRender.com). The red arrows represent the interactions between different components, while the black arrows indicate substances (such as LPS) entering the bloodstream from the intestine.