A review of MASLD-related hepatocellular carcinoma: progress in pathogenesis, early detection, and therapeutic interventions

Abstract

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is continuously rising, evolving into a global health challenge. Concurrently, cases of hepatocellular carcinoma (HCC) associated with MASLD are also on the increase. Although traditional risk factors such as age, gender, and metabolic factors play significant roles in the development of HCC, it cannot be overlooked that MASLD, triggered by changes in modern lifestyle and dietary habits, may also exacerbate the risk of HCC, and this phenomenon is common even among non-obese individuals. Regrettably, MASLD often fails to receive timely diagnosis, resulting in a limited number of patients receiving HCC surveillance. Moreover, there is currently a lack of clear definition for the target population for surveillance beyond patients with cirrhosis. Consequently, MASLD-related HCC is often detected at a late stage, precluding the optimal timing for curative treatment. However, our understanding of the pathogenesis and progression of HCC remains limited. Therefore, this paper reviews relevant literature from recent years, delving into multiple dimensions such as pathogenesis, surveillance and diagnosis, prevention, and treatment, aiming to provide new ideas and directions for the prevention and treatment of MASLD-related HCC.

Keywords: hepatocellular carcinoma; inflammatory response; metabolic dysfunction-associated steatotic liver disease; oxidative stress; the intestinal microbiome.

Figure 1

The pathogenesis of MASLD-related HCC includes insulin resistance, inflammation, oxidative stress and gut microbiota. The down regulation of IRS-2 leads to the over expression of SREBP-1 and the up-regulation of DNL, which leads to inflammatory response and oxidative stress. TDCA and TLCA in intestinal epithelial cells interact with bile acid receptors, resulting in FGF-15 and GLP-1 decline. IRS-2, insulin receptor substrate 2; SREBR-1, sterol regulatory element-binding protein 1; DNL, de novo lipogenesis; FFAs, free fatty acids; IGF, insulin-like growth factor; ACLY, ATP citrate lyase; SCD1, stearoyl coenzyme A desaturase-1; TNF-a, tumor necrosis factor alpha; IL-6, Interleukin 6; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; TCA, taurocholic acid; VDR, vitamin D receptor; PXR, pregnane X receptor; FXR, Farnesoid X nuclear receptor; TGR5, transmembrane G protein-coupled receptor 5; FGF15, fibroblast growth factor 15; GLP-1, glucagon-like peptide-1.

Figure 2

Treatment of MASLD-related HCC includes the following aspects: regulation of lipid metabolism, improvement of inflammatory response, mitigation of liver fibrosis, and intestinal microbia-related therapy. Glucose homeostasis and lipid synthesis were regulated by down-regulating SREBP-1C and ACC. Ly6c2 low-expressing restorative macrophages express regenerative growth factors and secrete anti-inflammatory cytokines. These cytokines may promote the apoptosis of activated hepatic stellate cells (HSCs) and the degradation of the extracellular matrix, thereby facilitating the resolution of inflammation. A dual C-C chemokine receptor type 2 and 5 antagonists significantly improved liver fibrosis, and antibiotics and pasteurization are used to regulate gut microbiota.

Figure 3

Prevention of the progression of MASLD-HCC should be carried out from the following three aspects: including diet, exercise and drugs. In terms of diet, low calorie diet can reduce the production of fat; Low carbohydrate and high protein diets reduce inflammation by improving microbiota and thereby serum folate levels, and the LCHF diet can reverse MASLD. Exercise can up-regulate antioxidant enzymes and anti-inflammatory mediators, improve mitochondrial protection, and thus reduce the risk of HCC. In terms of drugs, aspirin can selectively inhibit COX-2 and thus reduce liver fibrosis; pioglitazone can inhibit HSC activation and thus reduce HCC incidence; lipophilic statins can inhibit PKB pathway and reduce IL-6 production. HDL, high-density lipoprotein; GI, gastrointestinal; COX-2, cyclooxygenase-2; PPAR-γ, peroxisome proliferator-activated receptor gamma; MYC, MYC oncogene family; Akt, protein kinase B; NF-κB, nuclear factor kappa B; LCHF, low-carbohydrate high-fat diet.