Collin Reeves

Background: Hepatocellular carcinoma (HCC) is a devastating form of liver cancer that affects many people across the world.¹ HCC has a grim prognosis, with just under a 20% 5-year survival rate.^1,2 Early stages of HCC do not have well-defined clinical characteristics, which makes for a difficult diagnosis.³ As a result, patients present with advanced disease and ultimately have poorer survival outcomes.³ Current treatment diagnosis of HCC relies on invasive biopsy procedures, as there is a lack of a true, accurate prognostic factor.^1,2,3 Ferredoxin 1 (FDX1), along with other proteins and signaling pathways, has important roles in HCC and may prove beneficial as a potential prognostic factor.^4,5

Objective: We studied the physiological consequences of reduced FDX1 and how it promotes PI3K-AKT cellular signaling and other tumor-promoting mechanisms in hepatocellular carcinoma.

Search Methods: Using the PubMed database, the following terms were used to search for literature in the time frame of 2019-2025: “Hepatocellular Carcinoma”, “Ferredoxin 1”, “PI3K-AKT Signaling”, and “Sorafenib Resistance.”

Results: Studies show that FDX1-depleted tumor line PLC/PRF/5 displays increased tumor growth as compared to control samples.⁵ Conversely, in cell lines that overproduce FDX1, we see a decrease in tumor volume and growth.⁵ FDX1 is also shown to regulate mitophagy, and when knocked out, there is increased reactive oxygen species and ultimately tumor survival.⁵ The main mechanism by which tumor progression in HCC occurs is through the PI3K-AKT pathway, and loss of FDX1 increases p-AKT, thereby promoting cell growth.⁵ The highly used treatment Sorafenib stabilizes FDX1 and induces cell death.⁶ Upregulation of PI3K-AKT signaling in tumor cells may confer resistance to Sorafenib via FNDC5 expression.⁷ Hypoxic conditions stimulate the PI3K-AKT pathway through TUFT1 overproduction in HCC and may drive further resistance to Sorafenib. ^7,8 Transarterial chemoembolization (TACE) reduces HCC growth and metastasis while creating hypoxic conditions.⁹ Combined treatment of TACE and Sorafenib further improves treatment outcomes despite the hypoxic therapeutic paradox.^7,8,9 Levels of FDX1 have a positive correlation with overall survival and show positive traits for biomarker activity.¹⁰ FDX1 stands alone as a separate risk factor for more aggressive tumors.¹⁰

Conclusions: FDX1’s downregulation promotes tumor survival and proliferation in HCC through activation of PI3K-AKT signaling and mitochondrial dysfunction. FDX1 has significant potential as a diagnostic tool in HCC patients, and further research should focus on reliable, non-invasive measurement methods. Future targets for HCC therapy may revolve around restoring levels of FDX1 in FDX1-depleted patients susceptible to disease by providing patient-specific treatment. The therapeutic paradox highlighted between TACE and Sorafenib may indicate an area for improvement of current treatment regimens for patients with HCC.

Works Cited:

1. Philips CA, Rajesh S, Nair DC, Ahamed R, Abduljaleel JK, Augustine P. Hepatocellular Carcinoma in 2021: An Exhaustive Update. Cureus. Nov 2021;13(11):e19274. doi:10.7759/cureus.19274
2. Villanueva A. Hepatocellular Carcinoma. N Engl J Med. Apr 11 2019;380(15):1450-1462. doi:10.1056/NEJMra1713263
3. Alawyia B, Constantinou C. Hepatocellular Carcinoma: a Narrative Review on Current Knowledge and Future Prospects. Curr Treat Options Oncol. Jul 2023;24(7):711-724. doi:10.1007/s11864-023-01098-9
4. Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer and Metastasis Reviews. 2023/09/01 2023;42(3):629-652. doi:10.1007/s10555-023-10084-4
5. Sun B, Ding P, Song Y, et al. FDX1 downregulation activates mitophagy and the PI3K/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production. Redox Biol. Sep 2024;75:103302.doi:10.1016/j.redox.2024.103302
6. Wang W, Lu K, Jiang X, et al. Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer. J Exp Clin Cancer Res. Jun 6 2023;42(1):142. doi:10.1186/s13046-023-02720-2
7. Liu H, Zhao L, Wang M, et al. FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells. Front Oncol. 2022;12:852095. doi:10.3389/fonc.2022.852095
8. Dou C, Zhou Z, Xu Q, et al. Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca2+/PI3K/AKT pathway. Oncogene. 2019;38(8):1239-1255. doi:10.1038/s41388-018-0505-8
9. Kudo M, Ueshima K, Ikeda M, et al. Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma. Liver Cancer. 2022;11(4):354-367. Published 2022 Feb 10. doi:10.1159/000522547
10. Yue Q, Zhang M, Jiang W, et al. Prognostic value of FDX1, the cuprotosis key gene, and its prediction models across imaging modalities and histology. BMC Cancer. 2024;24(1):1381. Published 2024 Nov 11. doi:10.1186/s12885-024-13149-