NAFDL, recently re-named metabolic dysfunction-associated steatotic fatty liver disease (MASLD), even though the differences between the old and new acronym are negligible, is considered the most prevalent liver disease all over the world. We use the term NAFLD instead of MASLD throughout this text in light of the fact that the previous literature sources which we refer to use the old acronym [1]. What is more, the diagnostic terms “fatty liver”, “NAFLD”, and “NASH” were not associated with discomfort for the majority of patients. Although 26% of patients reported stigma related to overweight/obesity, only 8% disclosed a history of stigmatisation or discrimination due to NAFLD [2].

The risk factors of NAFLD are multiple and not always clearly defined, ranging from metabolic alterations (dyslipidaemia) to genetic/epigenetic traits [3], lifestyle modifications, including smoking [4], and even viral aetiology [5]. Obesity, mainly abdominal obesity, is one of the most important drivers [6]. Furthermore, patients with the severe form of NAFLD, i.e., nonalcoholic steatohepatitis (NASH) and obesity showed worsening of fibrosis versus those without obesity [7]. Still, sarcopenia is associated with increased risks of NAFLD and advanced fibrosis, independent of obesity or metabolic control [8]. Obviously, type 2 diabetes mellitus (T2DM) plays a determinant role, even though most clinical investigators suggest that NAFLD appearing first leads ultimately to the development of T2DM [9].

The mechanisms underlying NAFLD are even more complicated, including gene variants such as patatin-like phospholipase domain-containing protein 3, transmembrane 6 superfamily member 2, hydroxysteroid 17-beta dehydrogenase 13, membrane-bound O-acyltransferase domain-containing 7, and glucokinase regulator [10]. A key role is played by dysfunctional adipocytes, with the involvement of the mesenteric adipose tissue, adipokines such as adiponectin, the food intake hormone (leptin) and leptin resistance, as well as of another adipose tissue’s hormone, i.e., resistin [11]. It has been ascertained that insulin resistance (IR) is central to the onset and progression of NAFLD. Both innate and recruited immune cells, such as macrophages and T-cells, mediate the development of IR. Infiltrated macrophages in obese adipose tissue undergo a phenotypic switch from alternative M2 macrophages to classical M1 macrophages. Consequently, modifying the polarisation of resident and recruited macrophage/Kupffer cells is expected to pave the way to new therapeutic approaches in NAFLD [12]. Lipotoxicity is an important downstream signalling event. Free fatty acids (FFAs) activate apoptosis, including the up-regulation and increased number of death receptors such as Fas and TRAIL receptor 5, at the level of the plasma membrane, lysosomal permeabilisation, and endoplasmic reticulum stress, both coupled to mitochondrial dysfunction and in turn activating the mitochondrial pathway of apoptosis. Furthermore, FFAs set TLR4 signalling in motion, resulting in the up-regulation of several pro-inflammatory cytokines. Finally, other lipids such as free cholesterol and ceramide induce mitochondrial dysfunction and initiate the mitochondrial pathway of apoptosis [13]. Chronic low-grade inflammation represents a further mechanistic level of NAFLD. Inflammatory mediators that are biosynthesised in the liver and increased in NAFLD patients include C-reactive protein, interleukin (IL)-6, fibrinogen, and plasminogen activator inhibitor-1. Recent data lend credence to the fact that hepatic steatosis triggers IκB kinase-beta and nuclear factor-κB. Among the inducible transcription factors that control inflammatory gene expression, nuclear factor-κB plays a central and evolutionarily conserved role in coordinating the expression of various soluble pro-inflammatory mediators (cytokines and chemokines) and leukocyte adhesion molecules, as reviewed in [14]. Recent clues suggest that endoplasmic reticulum stress is involved in the development of lipid droplets and subsequent generation of reactive oxygen species (ROS) in the progression to NASH. The molecular processes caused by the disruption of endoplasmic reticulum homoeostasis, described as unfolded protein response, are associated with membrane biosynthesis, insulin action, inflammation, and apoptosis [15]. Gut microbiota dysbiosis significantly contributes to the pathogenesis and severity of NAFLD. Actually, relatively higher abundances of the genera Fusobacteria, and lower abundances of Oscillospira and Ruminococcus of Ruminococcaceae and Coprococcus of Lachnospiraceae, have been found in NAFLD patients, as well as other bacterial species such as Proteobacteria, Escherichia, and Enterobacteria. Also, Bacteroides were shown to be more frequent in patients with NASH. Another study showed the lower diversity of microbiota in the faeces of children with NAFLD and an increased number of Prevotellacopri. Finally, a low alpha bacterial diversity was linked with severe liver fibrosis, as reviewed in [16]. Other pathogenic factors and pathological mechanisms known to be involved in the complex disease progression of NAFLD involve programmed cell death include (j) autophagy of fat, referred to as lipophagy, that when impaired can lead to fat accumulation mediated by osteopontin, reduced levels of glycine N-methyltransferase, and phosphorylation of Jumonji-D3; (jj) ferroptosis, characterized by cytological changes that include reduced cell volume and increased mitochondrial membrane density, identified by iron dependence and lipid peroxidation; (jjj) apoptosis/necroptosis, whose key molecules include mixed lineage kinase domain-like and the receptor-interacting protein (RIP) protein kinase family members RIPK1 and RIPK3, with tumour necrosis factor receptor 1-mediated signal transduction being an example of the conversion between apoptosis and necroptosis; and (jjjj) pyroptosis, which may occur through the classic caspase 1-dependent pathway and the nonclassical caspase 4/5 (mouse caspase-11) pathway. All the above pathways are detailed in [17]. Mitochondrial dysfunction is a further molecular process leading to NAFLD due to the increased flux of FFAs in hepatocytes, which leads to increased mitochondrial fatty acid import and oxidation. Consequently, the overproduction of ROS damages mitochondrial membranes and may result in mitochondrial permeability transition pore formation with the consequent release of mtDNA in cytoplasm, which acts as a danger-associated molecular pattern and may activate the NLR family pyrin domain-containing 3 inflammasome with consequent maturation of the cytokine IL-1 beta and perpetuation of inflammation, with this latter mechanism being common to alcoholic liver disease [18]. Bile acids (BAs), beyond FFAs, hormone receptors and drugs, bind to nuclear receptors (NRs) and modulate their transcriptional activity. In hepatocytes and other cell types in the liver, NRs control multiple metabolic and inflammatory processes that influence the development of NAFLD/NASH [19]. It is essential to evidence that adiponectin is inversely linked to IR [20]. Glucocorticoids bear the potential to drive NAFLD, acting on both liver and adipose tissue. In their fasting state, they are able to mobilise lipids, increasing fatty acid delivery, and in their fed state, they can promote lipid accumulation [21]. Recent studies suggest that telomere shortening can lead to cellular dysfunction by impacting metabolism via a p53-dependent repression of mitochondrial biogenesis and function that results in dysfunctional mitochondria [22]. With NAFLD being more prevalent in the elderly [23], telomere length plays an important role in this very common liver disease in the sense that low length accounts for high NAFLD risk, making it plain that telomere shortening causes senescent cells to accumulate [24], Figure 1.