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THE KOREAN LIVER CANCER ASSOCIATION
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Original Article
- Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma
- Jin Sun Kim, Won-Mook Choi, Ha-Il Kim, Sung Won Chung, Jonggi Choi, Danbi Lee, Kang Mo Kim
- J Liver Cancer. 2025;25(1):79-90. Published online January 14, 2025
- DOI: https://doi.org/10.17998/jlc.2024.12.27
- 7,117 Views
- 124 Downloads
- 5 Web of Science
- 5 Citations
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Abstract
PDF - Backgrounds/Aims
Hepatocellular carcinoma (HCC) is a malignant cancer with an increasing incidence worldwide. Although numerous efforts have been made to identify effective therapies for HCC, current strategies have limitations. We present a new approach for targeting L-arginine and argininosuccinate synthetase 1 (ASS1).
Methods
ASS1 expression in HCC cell lines and primary hepatocytes was detected using polymerase chain reaction and western blotting. Proliferation, migration, signaling pathways, and nitric oxide production in HCC cell lines were measured using MTS, colony formation, wound healing, Western blot, and Griess assays.
Results
ASS1 expression varied among the HCC cell lines, and cisplatin cytotoxicity was ASS1-dependent. L-arginine alone induced apoptosis in HCC cell lines, regardless of ASS1 expression; however, its effect was enhanced in ASS1-expressing HCC cell lines. Cisplatin cytotoxicity also increased, suggesting that L-arginine acts as a sensitizer to cisplatin in HCC cell lines. ASS1 and L-arginine produced nitric oxide and inhibited key proliferation- and survival-related signaling pathways such as PI3K/Akt and MAPK. Additionally, ASS1 and L-arginine reduced the expression of PKM1 and PKM2 in the glycolysis pathway.
Conclusions
Our study revealed that ASS1 and L-arginine exhibited anticancer effects in HCC and sensitized cisplatin-resistant HCC cells to chemotherapy. The combination of ASS1 and L-arginine significantly enhanced the anticancer effects, even in HCC cell lines with low or absent ASS1 expression. These findings highlight the critical roles of arginine and ASS1 in HCC and suggest that increasing arginine availability could be a promising therapeutic strategy. -
Citations
Citations to this article as recorded by
- Metabolic-immune microenvironment crosstalk mediating ICI resistance in MASH-HCC
Yi Ju, Kequan Xu, Xi Chen, Tiangen Wu, Yufeng Yuan
Trends in Endocrinology & Metabolism.2026; 37(3): 262. CrossRef - L-Arginine as an Adjuvant Chemosensitizer: Enhancement of Intestinal Permeability and Cytotoxic Activity of Doxorubicin
Ghada Saad, Rana M. Alquwayi, Hanin B. Alanazi, Farah B. Aldahmashi, Aryam M. Alahmary, Shouq K. Almutairi, Fatima R. Alshammari, Ghadah T. Alshammari, Afnan J. Alrashidi, Norah K. Aldousari, Haifa F. Alsubiei, Lama H. Alanazi, Meaad H. Aldossary, Amal A.
Pharmaceuticals.2026; 19(4): 546. CrossRef - Impact of metabolic reprogramming on the immune response in hepatocellular carcinoma
Yang Wang, Yi-Jun Lu, Jian Zhou, Xin-Rong Yang
Hepatoma Research.2026;[Epub] CrossRef - Phytochemical Characterization and Antioxidant/Antitumoral Potential of Coffee Silverskin: Comparative Insights with Green and Roasted Coffee
Juliana A. Barreto-Peixoto, Cláudia Silva, Susana Machado, Maria Beatriz Prior Pinto Oliveira, Rita C. Alves, Fátima Martel, Nelson Andrade
Foods.2026; 15(14): 2447. CrossRef - Antitumor role of L-arginine and argininosuccinate synthetase 1 in hepatocellular carcinoma: direct and immunological mechanisms
Hyuk Soo Eun
Journal of Liver Cancer.2025; 25(1): 1. CrossRef
- Metabolic-immune microenvironment crosstalk mediating ICI resistance in MASH-HCC
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