Zachary McClarnon

Background: Liver cancer is one of the most common cancers globally. Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancers.¹ New HCC cases are projected to rise from 841,000 in 2018 to over 1 million annually by 2025.¹ With a 5-year survival rate of approximately 18%, HCC is the third leading cause of global cancer death. HCC is caused by chronic hepatocyte recycling, leading to DNA damage over time. Common risk factors include age, alcohol abuse, non-alcoholic fatty liver disease, viral infection, and telomerase reverse transcriptase mutations.¹ The current treatments for HCC are tumor resection, intra-arterial therapies, radiation, or systemic drug therapy, which includes Sorafenib (a multikinase inhibitor) and Lenvatinib.¹²³ These treatments kill HCC cells by inducing hypoxia and necrosis. However, this often leads to the upregulation of Hypoxia-Inducible Factor 1 alpha (HIF-1α), allowing HCCs to enter a pro-survival and drug-resistant state.⁴

Objective: In this narrative review, we explore the role of HIF-1α in HCC drug resistance as well as identify hypoxia and stemness markers for improved efficacy of frontline HCC treatments.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “Hepatocellular Carcinoma”, “HIF-1α”, “Drug Resistance”, “Sorafenib”, “Lenvatinib”, “HCC Treatment”, “HIF-1α Downregulation”.

Results: Ubiquitin-specific protease 22 (USP22) stabilizes HIF-1α, which is broken down by ubiquitination. Researchers studied the effects of removing USP22 on the levels of HIF-1α under hypoxic conditions. Their study showed that when USP22 was knocked out, there was a significant decrease in HIF-1α expression, thus confirming that USP22 plays a role in HIF-1α stabilization.⁵ Additionally, researchers wanted to determine USP22 knockout effects on HCC stemness and drug sensitivity. USP22 knockout reduced HCC proliferation (<20%) and CD24+ cells, while increasing Sorafenib-induced cell death.⁵ Previous research indicated that Metformin has anti-cancer effects through inhibition of HIF-1α.⁶ A randomized control trial consisting of 80 HCC patients was conducted to determine if a Metformin and Sorafenib combination therapy could improve outcomes. In both arms of the study, there was no difference in time to disease progression (p=0.3) or overall survival (p=0.6), indicating that the combination therapy was ineffective.⁷ Brucine D (BD) is a naturally occurring quassinoid that has demonstrated multiple anti-cancer effects.⁸ Additionally, researchers xenografted HCC tumors into nude mice and treated them with BD. The 1.5 mg/kg/day treatment group showed a significant decrease in HIF-1α expression, tumor weight, and tumor volume, without a significant change in overall body weight.⁸ Finally, researchers identified miR-138p-5p, a non-coding RNA that inhibits Enhancer of Zeste Homolog 2, a known transcriptional repressor that is upregulated in HCC.⁹ Their research showed that treatment with the miR-138p-5p mimic demonstrated a dose-dependent decline in HCC survival factors as well as a significant increase in the number of HCCs halted in the G0/G1 stage of the cell cycle when treated with radiation.⁹ Additionally, researchers showed this RNA mimic was able to decrease the levels of HIF-1α expression as well as reduce HCC’s ability to undergo epithelial-mesenchymal transition (EMT).⁹

Conclusions: HCC remains a globally prevalent and deadly cancer, with current therapies often undermined by hypoxia-induced HIF-1α upregulation and resulting drug resistance. Targeting HIF-1α stabilizers, such as USP22, shows promise in overcoming resistance. While Metformin demonstrates limited clinical utility, agents like Brucine D and non-coding RNAs may offer more effective, novel approaches to sensitizing HCC cells to treatment and improving therapeutic outcomes.

Works Cited:

1. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma [published correction appears in Nat Rev Dis Primers. 2024 Feb 12;10(1):10. doi: 10.1038/s41572-024-00500-6.]. Nat Rev Dis Primers. 2021;7(1):6. Published 2021 Jan 21. doi:10.1038/s41572-020-00240-3
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4. Bao MH, Wong CC. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells. 2021;10(7):1715. Published 2021 Jul 6. doi:10.3390/cells10071715
5. Ling S, Shan Q, Zhan Q, et al. USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut. 2020;69(7):1322-1334. doi:10.1136/gutjnl-2019-319616
6. Hu L, Zeng Z, Xia Q, et al. Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway. Life Sci. 2019;239:116966. doi:10.1016/j.lfs.2019.116966
7. El Shorbagy S, abuTaleb F, Labib HA, et al. Prognostic Significance of VEGF and HIF-1 α in Hepatocellular Carcinoma Patients Receiving Sorafenib Versus Metformin Sorafenib Combination. J Gastrointest Cancer. 2021;52(1):269-279. doi:10.1007/s12029-020-00389-w
8. Huang R, Zhang L, Jin J, et al. Bruceine D inhibits HIF-1α-mediated glucose metabolism in hepatocellular carcinoma by blocking ICAT/β-catenin interaction. Acta Pharm Sin B. 2021;11(11):3481-3492. doi:10.1016/j.apsb.2021.05.009
9. Bai B, Liu Y, Fu XM, et al. Dysregulation of EZH2/miR-138-5p Axis Contributes to Radiosensitivity in Hepatocellular Carcinoma Cell by Downregulating Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Oxid Med Cell Longev. 2022;2022:7608712. Published 2022 Aug 29. doi:10.1155/2022/7608712