Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators’ roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.

Cirrhosis represents the end stage of chronic liver injury, characterized by progressive fibrosis and architectural distortion that precipitate portal hypertension and systemic complications. Recent evidence positions gut microbiota dysbiosis and nitric oxide (NO) dysregulation as central, interacting pathophysiological mechanisms in cirrhosis progression. Intestinal barrier dysfunction facilitates bacterial translocation and thereby exposes the liver to lipopolysaccharides and pathogen-associated molecular patterns that trigger hepatic inflammation via Toll-like receptor signalling, a phenomenon aggravated by dysbiosis. This immune activation stimulates inducible NO synthase in Kupffer cells and systemic endothelium, generating excess NO that drives splanchnic vasodilation and worsens portal hypertension. Paradoxically, intrahepatic endothelial NO synthase activity becomes impaired, reducing sinusoidal NO availability and increasing intrahepatic vascular resistance. These interconnected disturbances perpetuate inflammation and fibrogenesis, contributing to cirrhosis decompensation and spontaneous bacterial peritonitis. Despite substantial mechanistic insight into these pathways, therapeutic translation remains limited. Statins show promise by restoring intrahepatic eNOS function and reducing portal pressure, while microbiota-targeted interventions (antibiotics, probiotics, fecal transplantation) address gut-derived inflammation. This review synthesizes our current understanding of the gut-liver-NO axis in cirrhosis, highlighting how dysbiosis and aberrant NO signalling reinforce each other through inflammatory feedback loops, and identifies critical gaps between mechanistic knowledge and clinical application that warrant further investigation.