Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1.

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Homeobox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Homeobox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition, with polycyclic aromatic hydrocarbons (PAHs) as a potential risk factor; however, the regulatory mechanisms remain unclear. PAH exposure oxidizes sphingosine-1-phosphate (S1P) lyase (S1PL) at position 317, reducing lyase activity and increasing S1P levels which is linked to MASLD progression. This study investigates how PAH exposure influences MASLD development and explores the role of S1PL and S1P in this process. C57BL/6J wild-type (WT) and mutant Sgpl1-knock-in (KI) (C317A, rendering resistance to oxidation) were fed either control diet (CD) or high-fat diet (HFD) for 8 weeks. Mice were treated with 500 μg/kg indeno(1,2,3-cd)pyrene (IP) every three days by oral gavage. Hepatocytes were isolated using classic two-step collagenase perfusion method and treated with IP or S1P. Increased lipid accumulation and upregulated S1P levels were observed in the MPH upon IP treatment. Reduced weight gain, fatty liver, and serum S1P levels were observed in Sgpl1-KI mice compared to those of WT mice upon HFD and IP treatments. Inhibition of S1PL increased lipid accumulation and S1P levels in Sgpl1-KI MPHs, whereas pharmacological inhibition of sphingosine kinase 1 (SPHK1), not SPHK2, decreased IP-induced lipid accumulation and S1P levels in WT MPH. S1P receptor 2 (S1pr2)-null MPHs developed alleviated IP-induced lipid accumulation as compared with WT MPHs. PAH elevated S1P via SphK1- and S1PL-mediated pathways, thereby increasing lipid accumulation through the S1P/S1PR2 axis in hepatocytes, worsening HFD-induced MASLD.