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Review
. 2024 Aug 8;10(1):356.
doi: 10.1038/s41420-024-02116-x.

Programmed cell death in hepatocellular carcinoma: mechanisms and therapeutic prospects

Xiang'an Wu #  1 , Jingying Cao #  2 , Xueshuai Wan  1 , Shunda Du  3
Affiliations
Review

Programmed cell death in hepatocellular carcinoma: mechanisms and therapeutic prospects

Xiang'an Wu et al. Cell Death Discov. .

Abstract

Hepatocellular Carcinoma (HCC), the most common primary liver cancer, ranks as the third most common cause of cancer-related deaths globally. A deeper understanding of the cell death mechanisms in HCC is essential for developing more effective treatment strategies. This review explores programmed cell death (PCD) pathways involved in HCC, including apoptosis, necroptosis, pyroptosis, ferroptosis, and immunogenic cell death (ICD). These mechanisms trigger specific cell death cascades that influence the development and progression of HCC. Although multiple PCD pathways are involved in HCC, shared cellular factors suggest a possible interplay between the different forms of cell death. However, the exact roles of different cell death pathways in HCC and which cell death pathway plays a major role remain unclear. This review also highlights how disruptions in cell death pathways are related to drug resistance in cancer therapy, promoting a combined approach of cell death induction and anti-tumor treatment to enhance therapeutic efficacy. Further research is required to unravel the complex interplay between cell death modalities in HCC, which may lead to innovative therapeutic breakthroughs.

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Conflict of interest statement

The authors declare no competing interests. All authors approved the final version for submission.

Figures

Fig. 1
Fig. 1. Intrinsic and extrinsic apoptosis in HCC.
Intrinsic apoptosis is triggered by stress or DNA damage, activating BH3-only proteins that bind with BCL-2 proteins to form BAX/BAX oligomers, leading to mitochondrial permeability and the release of apoptotic factors. In HCC, it is regulated by signaling pathways like CXCL1/2-CXCR2-ERK. The extrinsic pathway is mediated by death receptor signaling and specific death ligands, forming trimers that activate caspase cascades, IKK/NF-κB, and JNK pathways. The IKK/NF-κB pathway promotes cell survival and inhibits JNK-mediated apoptosis. tBID from the extrinsic pathway can bind with BAX and BAK1 to form MOMP. Apoptosis promotes HCC formation but inhibits it afterward. Drugs like sorafenib can promote apoptosis for anti-tumor effects.
Fig. 2
Fig. 2. The necroptosis mechanism in HCC.
Necroptosis is triggered by death receptors (FAS, TNFR1, TRAILR), TLR, or viruses, which activate RIPK3 through RIPK1, TICAM1, and ZBP1, leading to MLKL activation. This causes the plasma membrane to break and release cell contents. Necroptosis can hinder HCC cell survival but may cause chronic inflammation in hepatocytes. Lower levels of RIPK3 can activate a nonlethal necroptotic NF-κB pathway that can promote HCC progression. Necroptosis also influences HCC development through the regulation of TME and can be influenced by drugs or other signaling molecules.
Fig. 3
Fig. 3. The pyroptosis mechanism in HCC.
Pyroptosis is triggered by inflammasome activation, resulting in the cleavage of GSDMD by CASP1 or CASP11 to form GSDMD-C and GSDMD-N. GSDMD-N creates pores in the cell membrane, causing it to rupture, while GSDMD-C inhibits this process. Caspase-3 can also induce pyroptosis by cleaving GSDME to generate GSDME-N pores on the cell membrane. Pyroptosis helps prevent tumor growth and is controlled by various molecules and drugs. However, the Caspase-1 pathway of pyroptosis can increase levels of IL-1β and IL-18, promoting HCC progression. Additionally, iRFA-induced pyroptosis can lead to the production of PD-L1, aiding in the immune evasion of liver cancer cells.
Fig. 4
Fig. 4. The ferroptosis mechanism in HCC.
Ferroptosis is primarily induced by lipid peroxidation driven by iron overload and oxidative stress and is regulated by three major systems: the cysteine/GSH/GPX4 axis, the NAD(P)H/FSP1/CoQ10 system, and the GCH1/BH4/DHFR system. Ferroptosis is also regulated by various factors, including phosphorylation, acetylation, methylation, ncRNAs, ER stress, and mitochondrial proteins, thereby modulating the progression of HCC. Anti-tumor treatments for HCC operate by modulating these pathways, and disruption of these pathways may lead to drug resistance.
Fig. 5
Fig. 5. The ICD mechanism in HCC.
ICD refers to the initiation of innate and adaptive immune responses triggered by selected anticancer therapies, resulting in the production of specific CD8 + T lymphocytes that induce cell death through immune cytotoxicity, and concurrently activating DCs to enhance anti-tumor immunity. Inhibition of STAT3 and CD47 aslso play an important role in inducing the ICD of HCC cells.
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References

    1. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380:1450–62. 10.1056/NEJMra1713263 - DOI - PubMed
    1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. 10.3322/caac.21834 - DOI - PubMed
    1. Jose A, Bavetta MG, Martinelli E, Bronte F, Giunta EF, Manu KA. Hepatocellular carcinoma: current therapeutic algorithm for localized and advanced disease. J Oncol. 2022;2022:3817724. 10.1155/2022/3817724 - DOI - PMC - PubMed
    1. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80. 10.1002/hep.29086 - DOI - PubMed
    1. Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, Reeves HL, Wang XW, et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat Cancer. 2022;3:386–401. 10.1038/s43018-022-00357-2 - DOI - PMC - PubMed

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