The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies.

Hydrodynamics-based delivery has been used as an experimental tool to express transgene in small animals. This in vivo gene transfer method is useful for functional analysis of genetic elements, therapeutic effect of oligonucleotides, and cancer cells to establish the metastatic cancer animal model for experimental research. Recent progress in the development of image-guided procedure for hydrodynamics-based gene delivery in large animals directly supports the clinical applicability of this technique. This review summarizes the current status and recent progress in the development of hydrodynamics-based gene delivery and discusses the future directions for its clinical application.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are spreading worldwide as the most critical causes of cirrhosis and hepatocellular carcinoma (HCC). Thus, improving the screening and managing strategies for patients with MASLD or MASH is necessary. A traditional non-systemic review provided this narrative. Genetic variations associated with the development of MASLD and MASH, such as PNPLA3, TM6SF2, GCKR, MBOAT7, MERTK, and HSD17B13, were initially reviewed. PNPLA3 genetic variants appeared to be strongly associated with the increased pathogenesis of MASLD, MASH, cirrhosis, and HCC. We also reviewed the useful polygenic risk score (PRS) for the development of MASLD, MASH, their related cirrhosis, and the occurrence of HCC. PRSs appeared to be better predictors of MASLD, MASH, the development of cirrhosis, and the occurrence of HCC in patients with MASLD or MASH than any single-nucleotide polymorphisms. RNA interference and antisense nucleotides against the genetic variations of PNPLA3 and HSD17B13 are also being developed. Multidisciplinary collaboration and cooperation involving hepatologists, geneticists, pharmacologists, and pathologists should resolve complicated problems in MASLD and MASH. This narrative review highlights the importance of the genetic susceptibility and PRS as predictive markers and personalized medicine for patients with MASLD or MASH in the future.

Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC.

Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases.