**8. Conclusions and Challenges for the Future**

HCC primarily develops from cirrhosis, and these two diseases cause more than two million fatalities annually around the world. Since liver cirrhosis and HCC have limited available treatments, it is crucial to stop the spread of these diseases as early as possible. In recent years, it has become evident that the gut microbiota, via the gut–liver axis, significantly contributes to the development of HCC. Dysbiosis can be caused by a variety of lifestyle variables, and it has been shown in numerous human trials and animal studies that short-term treatment with probiotics or synbiotics can reverse dysbiosis and consequently enhance liver health. Fatty liver disease is one instance where this is especially accurate. As a means to interfere with the effects of dysbiosis, TLR4 inhibitors are expected to enter clinical development. A possible method of lowering the occurrence of HCC is to prevent the early onset of progressive liver disease through the microbiome. Probiotics and synbiotics, as well as dietary changes, are possible methods for achieving this. As addressed above, the technological advances in liver cancer biomarker profiling have provided a breakthrough in liver metabolomics research.

In addition, challenges connected to HCC metabolism, cellular interfaces, metabolomics, and metabolic changes have been addressed. Future review research initiatives are proposed for improving HCC performances with clinical metabolomics:


**Author Contributions:** Conceptualization, R.G.; writing—original draft preparation, R.G.; writing review and editing, R.G., S.J.Y., and K.T.S.; supervision, K.T.S.; project administration, K.T.S.; funding acquisition, K.T.S. All authors have read and agreed to the final version of the manuscript.

**Funding:** This research was funded by the Hallym University Research Fund and the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education, Science, and Technology (NRF-2018M3A9F3020956, NRF-2019R1I1A3A01060447, NRF-2020R1I1A3073530, and NRF-2020R1A6A1A03043026). This work was also supported by the Promotion of Innovative Businesses for Regulation-Free Special Zones, funded by the Ministry of SMEs and Startups (MSS, Korea) (P0020622).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data are contained within the article.

**Acknowledgments:** Ki Tae Suk would like to thank the NRF of Korea, the Ministry of Education, Science, and Technology, and the Ministry of SMEs and Startups (MSS) for the funding support. R.G. specially thanks Ki Tae Suk for his support.

**Conflicts of Interest:** The authors declare no conflict of interest.
