New therapeutic target for alcohol-associated hepatitis (AH): AH-associated IL-8+ neutrophils

Alcohol-associated liver disease (ALD) is one of the leading chronic liver diseases worldwide, encompassing a spectrum of conditions from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma.1 Histologically, alcohol-associated steatohepatitis (ASH) is characterised by lipid accumulation in hepatocytes, hepatocellular damage, ballooning of hepatocytes, formation of Mallory-Denk bodies, inflammation and pericellular fibrosis.1 Over the past several decades, research has elucidated key molecular mechanisms underlying ALD, such as ethanol-induced hepatotoxicity, oxidative stress, endoplasmic reticulum stress and organ–organ crosstalk pathways like the gut-liver and adipose tissue-liver axes.2 Patients with underlying chronic ALD, particularly those with recent episodes of excessive drinking, are at risk of developing acute alcohol-associated hepatitis (AH), a condition characterised by severe clinical symptoms, including jaundice.3 Severe AH (sAH) is commonly linked to alcohol-associated cirrhosis (AC) and carries a high short-term mortality rate. Due to the limited availability of effective pharmacological therapies, early liver transplantation is frequently required as a life-saving intervention.3 Identifying molecular mechanisms driving AH progression and liver failure is thus essential for developing targeted therapies for this life-threatening disease. AH, first described in 1961, is recognised as an acute inflammatory liver disease characterised by extensive inflammatory cell infiltration.4 Currently, AH is recognised as a form of acute-on-chronic liver injury involving various types of immune cells, including macrophages, neutrophils, T cells and B cells, as evidenced by immunohistochemical analysis.5 Recent RNA-sequencing analyses have highlighted that AH is associated with the upregulation of numerous inflammatory mediators, including pro-inflammatory cytokines, chemokines and adhesion molecules.5–7 However, the key mechanisms that drive the transition from ALD to sAH remain unclear.