Evan Zuo

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, primarily due to its poor prognosis and ineffective diagnosis due to nonspecific symptoms early on.^1,5,9 One of the primary drivers for HCC is chronic alcohol consumption.^1,5,6 Alcohol is normally metabolized to acetaldehyde, a carcinogen whose subsequent breakdown is catalyzed by ALDH2.^1,5,7 Unfortunately, it is estimated that roughly 1 billion people in the world carry the rs671 polymorphism in the ALDH2 gene, leading to ALDH2 deficiency.^1,5,8 This results in buildup of acetaldehyde after alcohol consumption, which contributes significantly to the development and progression of alcohol-associated HCC.^1,5,7 Therefore, it is critical to study ALDH2 and its role in various metabolic pathways in order to elucidate how they affect HCC development, growth, means of immune escape, and metastasis.

Objective: In this narrative review, we investigated the mechanisms of how deficiencies in ALDH2 lead to altered activities in various biochemical pathways involved with hepatocellular carcinoma as well as a potential drug therapy that could reduce the risk for this cancer.

Search Methods: An online search in the PubMed database and the Journal of Hepatology database was conducted from 2017 to 2024 using the following keywords: “ALDH2”, “alcohol”, “hepatocellular carcinoma”.

Results: Studies show that liver hepatocellular carcinoma (LIHC) cell lines were associated with high levels of acetaldehyde and deficiencies in ALDH2.³ The buildup of acetaldehyde leads to increased reactive oxygen species (ROS), high amounts of markers of oxidative stress such as MDA, and low levels of antioxidants like superoxide dismutase.^2,3 These conditions lead to the packaging of oxidized mitochondrial DNA into extracellular vesicles, which are transferred to neighboring hepatocytes, where they activate carcinogenic pathways like TAZ and BCL-2 that can trigger HCC development.^1,2,3 ALDH2 deficiency can also contribute to HCC progression through the loss of autophagy and increased immune escape. With low ALDH2, oxidative stress activates Nrf2, which inhibits autophagy of HCC cells.³ Furthermore, Nrf2 overexpression results in less susceptibility to T-cell killing, allowing cancer cells to escape the immune system.³ Loss of ALDH2 can also promote the growth of HCC tumors through its effects on the SLC3A2, a gene involved with sphingolipid biosynthesis.² Without the inhibitory effects of ALDH2 on SLC3A2, carcinogenic metabolites like S1PR1 and ceramide accumulate, which promotes HCC tumor growth.² ALDH2 can also increase expression of AMPK, which decreases metastasis of HCC cells.⁴ Therefore, when cells were treated with Metformin and AICAR (both are AMPK activators), HCC cells showed decreased migratory and invasive capacity.⁴ With ALDH2 playing critical roles in multiple aspects of HCC, the therapeutic potential of Essential AD2 was evaluated. Essential AD2 was found to significantly decrease serum acetaldehyde levels in ALDH2 deficient patients with no major adverse side effects.⁵

Conclusions: Studies have discovered that deficiencies in ALDH2 can lead to the development, growth, immune escape, and metastasis of hepatocellular carcinoma. Additionally, the usage of Essential AD2 has shown promise in reducing blood acetaldehyde levels.The role of ALDH2 and efficacy of Essential AD2 could lead to new therapies for prophylaxis or treatment of HCC.

Works Cited:

1. Seo W, Gao Y, He Y, et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. Journal of Hepatology. 2019;71(5):1000-1011. doi:10.1016/j.jhep.2019.06.018
2. Xia P, Liu DH, Wang D, Wen GM, Zhao ZY. SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway. Free Radical Biology and Medicine. 2023;206:125-133. doi:10.1016/j.freeradbiomed.2023.07.002
3. Hu J, Yang L, Peng X, et al. ALDH2 Hampers Immune Escape in Liver Hepatocellular Carcinoma through ROS/Nrf2-mediated Autophagy. Inflammation. 2022;45(6):2309-2324. doi:10.1007/s10753-022-01694-1
4. Hou G, Chen L, Liu G, et al. Aldehyde dehydrogenase-2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice. Hepatology. 2017;65(5):1628-1644. doi:10.1002/hep.29006
5. Fujioka K, Gordon S. Effects of “Essential AD2” Supplement on Blood Acetaldehyde Levels in Individuals Who Have Aldehyde Dehydrogenase (ALDH2) Deficiency. American Journal of Therapeutics. 2019;26(5):e583-e588. doi:10.1097/mjt.0000000000000744
6. Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. Journal of Hepatology. 2019;70(2):284-293. doi:https://doi.org/10.1016/j.jhep.2018.10.008
7. Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. Journal of Clinical and Translational Hepatology. 2021;000(000):1-9. doi:10.14218/jcth.2020.00104
8. Liu Y, Liu T, Zhang F, Gao Y. Unraveling the Complex Interplay between Epigenetics and Immunity in Alcohol-Associated Liver Disease: A Comprehensive Review. International journal of biological sciences. 2023;19(15):4811-4830. doi:10.7150/ijbs.87975
9. Dimitroulis D, Damaskos C, Valsami S, et al. From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. World Journal of Gastroenterology. 2017;23(29):5282-5294. doi:10.3748/wjg.v23.i29.5282