A wealth of studies of the various dysfunctional organs and cell types that contribute to progression of NAFLD has led to the identification of multiple signalling and metabolic pathways that promote liver dysfunction and fibrosis29,30,31. Among these, insulin resistance is a major initiating pathological event that drives de novo lipogenesis in the liver29,30,31. Multiple physiological differences between the sexes lead, either directly or indirectly, to increased whole-body insulin sensitivity in women, which is generally considered to promote liver homeostasis. White adipose tissue (WAT) depots in women are primarily subcutaneous, have high expandability and produce substantial amounts of the insulin-sensitizing hormone adiponectin. Moreover, the increased insulin sensitivity of skeletal muscle in pre-menopausal women is associated with an increased capacity for triglyceride extraction. These features confer on women an advantageous metabolic adaptability to lipid overload32. By contrast, WAT depots in men are primarily visceral, produce pro-inflammatory cytokines and are associated with cardiometabolic diseases32.

In addition, sex is rarely considered as a biological variable in these numerous and interesting studies, despite the reported sexual dimorphism of the gut microbiota36, innate immune system37, skeletal muscle and adipose tissues32, and the liver itself

In general, men have more advanced grades of NASH than women98,99, and men are also more prone than women to develop fibrosis100. NASH-related HCC is diagnosed 2–4 times more often in men than women, and this sex bias is also observed in mouse studies, which suggests that the increased susceptibility to HCC observed in men101 is unlikely to be due to increased exposure to one or more risk factors102. This protection from the development of HCC is similarly unlikely to reflect a globally higher resistance of the female liver to injury, given that some other liver pathologies, such as alcoholic liver disease and primary biliary cirrhosis, develop more aggressively in women than in men103. As with the physiological aspects of liver sexual dimorphism, little is known of the intrinsic molecular mechanisms underlying the exacerbated development of NASH and its comorbidities in males.