The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

Keywords: HCC; MASH; MASLD; microenvironment; therapeutics.

Figure 1

The development of MASLD, MASH and HCC.

Figure 2

The parenchymal cells, non-parenchymal cells, and the extracellular matrix in the hepatic microenvironment function in the progression of MASLD, MASH, and MASH-HCC. Some cells have opposite effects in different phenotypes or disease stages, such as cx3cr1-expressing myeloid DCs can produce TNF-α to promote inflammation, while CD103+ dc plays a protective role in steatohepatitis by producing IL10. In addition, CD8T cells can not only promote the progression of NALFD by producing a series of inflammatory factors such as granase, TNF-α, IFN-γ, but also play an anti-inflammatory and anti-tumor role by producing IL-10 and perforin. M1 M1 macrophage, M2 M2 macrophage.