Searching for novel cellular targets for MASLD and HCC within the humble lysosomal cathepsins

Metabolic-associated steatotic liver disease (MASLD) and its pathological version, metabolic dysfunction-associated steatohepatitis (MASH), are becoming the main leading causes of chronic liver disease almost worldwide and are the fastest growing aetiology of hepatocellular carcinoma (HCC), especially in the Western countries. The combination of high incidence and morbidity with limited treatment options for both MASH and HCC highlights an urgent need for the discovery of novel therapeutic candidates to inform drug development. The importance of lysosomes and cathepsins, their most abundant hydrolases, has been overlooked for decades. They were considered organelles only involved in the recycling of macromolecules, with cathepsins simply being their effectors. Contrary to this traditional view, recent findings have shed new light on the lysosome and its enzymes as drivers of essential cellular processes, such as apoptosis and autophagy. Bringing lysosomal activity and the regulation of cathepsins into the spotlight of MASH and HCC research can open new avenues for the development of novel drugs based on targeting cathepsin-driven lysosomal activity and its associated pathological processes. This review comprehensively summarises the current knowledge on the role and contribution of lysosomal cathepsins to MASLD/MASH and HCC progression.