Cholesterol-LXR axis in metabolic regulation of liver fibrosis and hepatocarcinogenesis

Metabolic dysfunction-associated steatotic liver disease is increasing worldwide, and its progression to metabolic dysfunction-associated steatohepatitis (MASH) and ultimately hepatocellular carcinoma (HCC) remains a major clinical challenge. In this review, we discuss the role of liver X receptors (LXRs), transcriptional regulators of fatty acid synthesis, and cholesterol balance, which play an apparently paradoxical metabolic role: while their activation increases lipogenesis, driving steatosis, their inhibition leads to harmful cholesterol buildup and inflammation, central to the pathogenesis of MASH and HCC. In HCC, disrupted LXR signalling prevents cholesterol efflux, fuelling tumour growth. Therapeutic strategies targeting LXRs must therefore be stage-specific and cell type-specific to avoid worsening liver injury.