*3.4. STING*

In view of its recent discovery, there have been a limited number of human studies exploring the role of STING in CLD. Luo et al. reported an overexpression of STING in the non-parenchymal cells within the liver tissue of NAFLD patients, albeit with no examination of their relationship to disease activity [148]. By utilizing the alcohol-fed mouse ALD model, Petrasek et al. demonstrated that activation of the STING–IRF3 pathway stimulates pro-inflammatory cytokine production in the liver [149]. In the same study, alcohol-induced liver injury was also shown to trigger the STING–IRF3 pathway by endoplasmic reticulum (ER) stress, promoting the mitochondrial apoptotic pathway in hepatocytes [149]. Knocking out STING in HFD-induced NAFLD and MCD-induced NASH murine models attenuated hepatic activation of IRF3 and NF-κB pathways, and significantly downregulated expression of pro-inflammatory cytokines to alleviate NAFLD/NASH severity [148]. Similar findings were reported by Yu et al. using HFD- and MCD-diet-induced NASH mice; hepatocytes releasing mitochondrial DNA during NASH development led to the activation of STING–IRF3 pathway on KC to trigger pro-inflammatory cytokine production and hepatic inflammation in NASH [150].

Taken together, the above studies suggest that STING plays an important role in both hepatic inflammation and hepatic fibrosis in NASH [148,150]. Similar findings were elucidated in a CCL4-induced liver fibrosis murine model by Iracheta-Vellve et al. Hepatocytes were shown to undergo significant ER stress resulting in STING–IRF3 activation and induction of the mitochondria-dependent apoptosis pathway. Hepatocyte cell death was shown to activate HSC expression of α-SMA and COL1A2, collagen deposition, and fibrosis progression [151].

### **4. Therapies to Prevent Microbe-Driven Liver Inflammation and Fibrosis**

The primary interventions for alcoholic and fatty liver disease have focused on lifestyle modifications: abstaining from alcohol and improving patient diet and exercise regimens. In more severe cases of obesity, surgical interventions (e.g., bariatric surgery) are required in combination with significant lifestyle adjustments. Unfortunately, even in the case of surgical interventions, patient compliance towards dietary and alcohol restrictions is often lacking, rendering the development of novel therapeutics a top priority.

In cirrhotic patients, dietary interventions and abstinence from alcohol drastically improve survival [162]. These patients also generally require treatment of portal hypertension, which is the contributing factor to intestinal permeability. Unfortunately, however, in decompensated cirrhosis, treatment of portal hypertension using beta-blockers and anti-hypertensives can dangerously reduce mean arterial pressure [163]. In addition, there is an increased risk of susceptibility to infections due to poor phagocytic capacity in the liver and increased likelihood of ascites: the accumulation of fluid in the peritoneal cavity [3]. These aspects further underline the vital need for novel therapies to prevent the progression of fibrosis, particularly in end-stage liver disease where there is currently a lack of effective treatment. Limiting the exacerbation of inflammation and fibrosis by microbial translocation into the liver is therefore an avenue that must be explored. We aimed to summarize current and potential therapies directed at (1) reducing microbial translocation, and (2) limiting the harmful response to microbial antigens in the liver.
