Liver Steatosis: From Lipotoxicity to Cellular Damage

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most common cause of chronic liver disease [1]. MASLD is defined by hepatic steatosis in the presence of cardiometabolic risk factors (i.e., obesity, type 2 diabetes/glucose intolerance, hypertension, dyslipidemia), and its prevalence is expected to rise further in the near future, therefore representing a major global health burden [2, 3]. Of note, MASLD—formerly termed “Nonalcoholic fatty liver disease (NAFLD)”—allows the consumption of alcohol amounts up to 140 g/wk. for female and 210 g/wk. for male individuals [4]. Chronic, low-grade, sterile inflammation, which is orchestrated by parenchymal (mainly hepatocytes) and non-parenchymal resident or freshly infiltrated immune cells (e.g., macrophages, neutrophils, hepatic stellate cells [HSCs]), is the key driver of progression to metabolic dysfunction-associated steatohepatitis (MASH; formerly referred to as nonalcoholic steatohepatitis [NASH]) and liver fibrosis [5, 6]. Meta-analyses reveal that progression of fibrosis is influenced by extrinsic (e.g., genetics, sex, age) and intrinsic (e.g., lifestyle factors, dietary habits, gut microbiota) risk factors [7], while fibrosis stage correlates with disease-related morbidity and mortality among MASH patients and is associated with liver cirrhosis or hepatocellular carcinoma (HCC) [8, 9]. Given that heterogeneity of MASLD in respect of modifiable and non-modifiable factors or extrahepatic disease drivers contributing to conditions like MASLD such as in the gastrointestinal tract, adipose tissue, or the endocrine system, there is ongoing exploration into targeting these mediators for the treatment of MASH. Although extensive pathomechanistic insights over the last decades led to the successful identification of pharmacologic targets impeding the development of promising drug candidates, most advanced approaches particularly focus on metabolic pathways to mitigate the detrimental effects on hepatocytes, thereby dampening subsequent inflammatory and fibrogenic signals indirectly [10]. This had led to the approval of the first MASH-targeting therapy, resmetirom, as discussed below. The in-depth understanding of metabolic, inflammatory and fibrogenic pathways in MASLD/MASH is expected to fuel the development of further, even more effective therapeutics.