The application prospects of L-Arginine in the treatment of liver diseases

As a semi-essential amino acid in the human body, L-arginine is not only a key precursor for protein synthesis but also a core substrate for the synthesis of endogenous nitric oxide (NO), urea, and polyamines. Its metabolic process in the liver is closely related to liver function maintenance, hepatocyte repair, and the homeostasis of the intrahepatic microenvironment. Based on the differences in the pathological mechanisms of liver diseases (such as hepatitis, liver fibrosis, liver cirrhosis, and liver failure), L-arginine demonstrates multi-dimensional therapeutic potential by regulating the NO signaling pathway, improving hepatic blood supply, inhibiting inflammatory responses, and promoting hepatocyte regeneration. Its application prospects can be analyzed in combination with specific types of liver diseases and their mechanisms of action:

I. Application Potential in Viral Hepatitis and Alcoholic/Non-Alcoholic Fatty Liver Disease (ALD/NAFLD)

The core pathological features of viral hepatitis (e.g., hepatitis B, hepatitis C) and ALD/NAFLD are inflammatory damage to hepatocytes and lipid metabolism disorders. L-arginine can alleviate the progression of lesions through a dual mechanism:

On one hand, NO produced by L-arginine under the catalysis of nitric oxide synthase (NOS) can inhibit the activation of intrahepatic Kupffer cells (liver macrophages), reduce the release of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and downregulate the activity of inflammatory signaling pathways (e.g., NF-κB) in hepatocytes, thereby alleviating inflammation-mediated hepatocyte apoptosis. For example, in a rat model of alcoholic fatty liver, supplementation with L-arginine reduced TNF-α levels in liver tissue by 40%–50%, decreased the area of hepatocyte steatosis by more than 30%, promoted the repair of mitochondrial function (reducing damage to mitochondria caused by acetaldehyde, a metabolite of alcohol), and improved the efficiency of lipid oxidative metabolism.

On the other hand, for non-alcoholic fatty liver disease (NAFLD), L-arginine can promote the transport of triglycerides out of hepatocytes by regulating the expression of lipid transport-related proteins in the liver (e.g., apolipoprotein B100). At the same time, it inhibits the activity of key enzymes in fatty acid synthesis (e.g., acetyl-CoA carboxylase) to reduce lipid accumulation in hepatocytes. In addition, NO can dilate hepatic sinusoidal endothelial cells, improve intrahepatic microcirculation, and provide more sufficient oxygen and nutrients to hepatocytes, alleviating lipid metabolism disorders exacerbated by ischemia and hypoxia.

Current preclinical studies have confirmed that L-arginine combined with hepatoprotective drugs (e.g., silymarin) can improve liver function indicators in NAFLD patients (e.g., ALT and AST levels decrease by 20%–25%). However, clinical research on viral hepatitis is still in the early stages, and further verification of its synergistic effect with antiviral drugs (e.g., nucleoside analogs) is needed.

II. Core Value in the Treatment of Liver Fibrosis and Liver Cirrhosis

Liver fibrosis is a key intermediate stage in the progression of chronic liver disease to cirrhosis. Its essence is the activation of hepatic stellate cells (HSCs) after hepatocyte damage, which synthesize a large amount of collagen fibers, leading to the remodeling of liver tissue structure. The role of L-arginine in this process mainly focuses on "inhibiting the progression of fibrosis" and "improving complications of cirrhosis":

1. Inhibiting HSC Activation and Collagen Deposition

Activated HSCs are the main effector cells of liver fibrosis. NO can inhibit the proliferation of HSCs and the signal transduction of transforming growth factor-β1 (TGF-β1, a core cytokine promoting HSC activation), thereby reducing the synthesis and secretion of type I and type III collagen. Meanwhile, as a precursor for the synthesis of polyamines (e.g., putrescine, spermidine), L-arginine enables polyamines to regulate the apoptotic signaling pathway of HSCs, promote the apoptosis of activated HSCs, and reduce the source of collagen fibers. In a rat model of liver fibrosis, long-term supplementation with L-arginine reduced collagen content in liver tissue by 35%–40% and decreased the liver fibrosis stage (e.g., Ishak score) by an average of 1–2 grades.

2. Improving Portal Hypertension and Liver Function in Cirrhosis

Patients with cirrhosis often develop portal hypertension due to damage to hepatic sinusoidal endothelial cells and increased intrahepatic vascular resistance, which in turn leads to complications such as esophagogastric varices and ascites. NO produced by L-arginine can specifically dilate intrahepatic resistance vessels (e.g., hepatic sinusoids, portal vein branches) and reduce portal pressure (preclinical studies show that portal pressure can decrease by 20%–25%). At the same time, it improves the "fenestrated structure" of hepatic sinusoidal endothelial cells (reducing hepatic sinusoidal capillarization), restores the efficiency of material exchange between hepatocytes and blood, and alleviates liver failure (e.g., increasing serum albumin levels, reducing prothrombin time).

It should be noted that patients with decompensated cirrhosis may experience the "arginine paradox"—that is, intrahepatic NOS activity decreases (due to reduced enzyme synthesis caused by hepatocyte damage). Simple supplementation of L-arginine may not effectively produce NO, and it is necessary to combine it with NOS coenzymes (e.g., tetrahydrobiopterin) to improve NO synthesis efficiency. This is also a direction that needs optimization in future clinical applications.

III. Adjuvant Therapeutic Prospects in Liver Failure and Perioperative Period of Liver Transplantation

The core challenges in acute liver failure (e.g., drug-induced liver failure) and the perioperative period of liver transplantation are massive hepatocyte necrosis, a sharp decline in liver function, and postoperative ischemia-reperfusion injury. L-arginine can act as an adjuvant therapy to "protect hepatocytes" and "improve transplantation prognosis":

1. Hepatocyte Protection in Acute Liver Failure

L-arginine can not only dilate intrahepatic blood vessels and improve ischemia and hypoxia through NO but also increase the level of glutathione (GSH, an important antioxidant) in hepatocytes, reducing oxidative damage to hepatocytes caused by reactive oxygen species (ROS). Meanwhile, its metabolite urea can promote the clearance of toxic substances (e.g., ammonia) in the liver and alleviate symptoms of hepatic encephalopathy (a common complication of liver failure). In a mouse model of acetaminophen-induced acute liver failure, supplementation with L-arginine reduced hepatocyte necrosis by 50%, increased mouse survival rate by 40%, and significantly reduced blood ammonia levels (reducing the toxicity of ammonia to the central nervous system).

2. Protective Effect During the Perioperative Period of Liver Transplantation

Ischemia-reperfusion injury (IRI) during liver transplantation is an important cause of primary non-function of the transplanted liver. NO can alleviate IRI-induced damage to the transplanted liver by inhibiting neutrophil infiltration, reducing ROS production, and inhibiting platelet aggregation. In addition, L-arginine can promote the regeneration of hepatocytes in the transplanted liver (by activating cell cycle-related proteins such as Cyclin D1) and accelerate the recovery of liver function. Clinical studies have shown that short-term supplementation of L-arginine before and after liver transplantation can increase the bile secretion of the transplanted liver (a key indicator reflecting liver function) by 30% within 24 hours after surgery, shorten the patient's hospital stay by an average of 3–5 days, and reduce the incidence of postoperative infections.

IV. Application Limitations and Future Optimization Directions

Although L-arginine has shown clear potential in the treatment of liver diseases, its clinical application still has limitations that need to be addressed:

1. Precision of Dosage and Administration Route

The demand for L-arginine varies greatly among different stages of liver disease (e.g., compensated cirrhosis vs. decompensated cirrhosis). Excessive supplementation may lead to hyperammonemia (especially when liver urea synthesis function is impaired in patients with liver failure) or hypotension caused by excessive NO production. Therefore, individualized dosages need to be formulated based on the patient's liver function indicators (e.g., Child-Pugh classification). In addition, oral L-arginine is easily decomposed into ammonia by intestinal bacteria (which may exacerbate hepatic encephalopathy). In the future, formulations with higher intestinal absorption efficiency (e.g., enteric-coated formulations) can be developed, or intravenous infusion (suitable for patients with severe liver disease) can be used.

2. Synergistic Effect of Combined Therapy

The therapeutic effect of L-arginine used alone is limited, and it is necessary to explore its synergistic effect with other treatment methods—for example, combining with hepatoprotective drugs (e.g., silymarin), anti-fibrotic drugs (e.g., pirfenidone), or probiotics (regulating intestinal flora to reduce intestinal decomposition of L-arginine) to further improve efficacy.

3. Improvement of Clinical Evidence

Most current studies focus on the preclinical stage, and there are still few large-sample, multi-center randomized controlled trials (RCTs) for different liver diseases, especially the lack of long-term safety data (e.g., the impact of long-term supplementation on renal function). Higher-quality clinical studies are needed to verify its efficacy and safety.

With its multiple roles in regulating intrahepatic NO levels, inhibiting inflammation, improving microcirculation, and promoting hepatocyte regeneration, L-arginine has shown clear therapeutic prospects in scenarios such as viral hepatitis, ALD/NAFLD, liver fibrosis, liver cirrhosis, and the perioperative period of liver transplantation. In the future, by optimizing administration regimens, exploring combined treatment strategies, and accumulating more clinical evidence, L-arginine is expected to become an important adjuvant in the comprehensive treatment of liver diseases, especially playing a key role in improving liver function, delaying disease progression, and reducing the incidence of complications.