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Novel diagnostic and therapeutic strategies based on PANoptosis for hepatocellular carcinoma

Jie Xiang, Yukai Li, Shengmin Mei, Zhiyan Ou, Li Wang, Yang Ke and Zhiwei Li
Cancer Biology & Medicine August 2025, 22 (8) 928-939; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0150

Abstract

Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, poses a large medical care burden worldwide. The prognosis of patients with HCC is poor, owing to recurrence and metastasis after common treatment methods. Therefore, identifying new targets to eliminate HCC cells is critical for treatment of HCC without recurrence. PANoptosis, a novel inflammatory cell death pathway, has become an intensively investigated area in recent years. The concept of PANoptosis has brought new hope for HCC therapy, given recent evidence implicating this form of programmed cell death in cancer progression, prognosis, and resistance to chemotherapy and immunotherapy. Despite increasing reviews describing the role of PANoptosis in various cancer types, to our knowledge, no systematic review has examined the implications of PANoptosis in HCC. Therefore, we sought to provide the first systematic review of the regulatory mechanisms and therapeutic potential of PANoptosis in HCC. We summarize recent progress in exploration of the role of PANoptosis in HCC, particularly regulation of the HCC tumor microenvironment by PANoptosis. Finally, we highlight the potential of PANoptosis-based diagnostic and therapeutic strategies for HCC.

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Introduction

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer that poses a substantial burden on medical care worldwide, particularly in China, where populations have high HCC risk because of the prevalence of hepatitis B virus infection1,2. Although the development of neonatal hepatitis B virus vaccination and effective anti-viral agents has decreased HCC incidence, other risk factors such as diabetes mellitus, obesity, and non-alcoholic fatty liver disease have recently contributed to an increase in HCC cases1,3,4. Moreover, HCC morbidity and mortality remain high, despite substantial prevention, early diagnosis, and treatment efforts5. The aggressive nature of HCC leads to poor patient prognosis, because of recurrence and metastasis after common treatment methods such as surgery, chemotherapy, or even recently proposed immunotherapy6–9. Therefore, identifying new targets to eliminate HCC cells is critical for treatment of HCC without recurrence.

In this context, the concept of PANoptosis has brought new hope for HCC therapy. PANoptosis, an inflammatory programmed cell death (PCD) pathway regulated by the PANoptosome complex, has key features of pyroptosis, apoptosis, and necroptosis that cannot be accounted for by any PCD pathway alone. Recent evidence has implicated PANoptosis in cancer progression, prognosis, and resistance to chemotherapy and immunotherapy10,11. To our knowledge, no published review has summarized the role of PANoptosis in HCC, although the implications of PANoptosis in other cancer types have recently been reviewed12–22.

Therefore, we aimed to provide the first systematic review of the regulatory mechanisms and therapeutic potential of PANoptosis in HCC. We summarize recent progress in exploration of the role of PANoptosis in HCC, particularly the regulation of the tumor microenvironment (TME) of HCC by PANoptosis. Finally, we highlight the potential of PANoptosis-based diagnostic and therapeutic strategies for HCC.

PANoptosis is a novel inflammatory cell death pathway incorporating all features of pyroptosis, apoptosis, and necroptosis

PCD is an essential mechanism for removing unnecessary or potentially harmful cells and maintaining homeostasis in the body23. Apoptosis, pyroptosis, and necroptosis are 3 key PCD types identified to date24. Notably, growing evidence indicates extensive crossover and crosstalk among these 3 PCD types. Therefore, Malireddi et al.25 proposed the concept of PANoptosis to integrate all these types of PCD. Moreover, the PANoptosome complex is defined as a molecular scaffold for contemporaneous engagement of key components involved in pyroptosis, apoptosis, and necroptosis26. The discovery of PANoptosis has provided novel insights into the crosstalk of various PCD pathways and aided in exploration of their roles in inflammatory cascades implicated in diverse diseases including cancer27.

Apoptosis, pyroptosis, and necroptosis have different genetic characteristics. Specifically, apoptosis pathways include exogenous apoptotic signaling mediated by the binding of ligands to death receptors, endogenous apoptotic signaling mediated by B-cell lymphoma-2 (Bcl-2) family proteins, and caspase-independent apoptotic signaling triggered by endoplasmic reticulum stress. Caspase activation is a key step in regulating apoptosis28. Pyroptosis, an inflammatory cell death pathway induced by the pore-forming activity of the gasdermin (GSDM) protein family, includes the classical pathway, which is triggered by inflammasomes and activates caspase-1, and the non-classical pathway, which is triggered by lipopolysaccharide and activates caspase-4/5/11. The activation of inflammasomes and the release of pro-inflammatory molecules such as Interleukin-1β/18 (IL-1β/18) are hallmarks of pyroptosis29. Necroptosis, a cell death pathway with morphological characteristics of necrotic cells but signaling mechanisms of apoptotic cells, is mediated by receptor-interacting serine/threonine protein kinase 1 (RIPK1), Receptor-interacting serine/threonine protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL)30.

The differences among apoptosis, pyroptosis, necroptosis, and PANoptosis have recently been discussed and are listed in Table 131. Recent evidence indicates crosstalk among apoptosis, pyroptosis, and necroptosis. Caspase-8 activation induces apoptosis. In contrast, caspase-8 cleaves and inactivates RIPK1 and RIPK3, 2 key proteins mediating the necroptotic pathway, as discussed above. Therefore, caspase-8 functions as a switch that promotes activation of apoptosis while preventing activation of necroptosis. When some pathogens or stimuli induce inactivation of caspase-8, RIPK1 and RIPK3 cleavage by caspase-8 is prevented, and these proteins subsequently bind MLKL, thus forming the necrosome and inducing necroptosis. In the crosstalk between pyroptosis and apoptosis, Caspase-1 functions as a switch. Caspase-1, a key mediator of pyroptosis, also activates apoptotic pathways in the absence of gasdermin D (GSDMD). GSDMD, a pore-forming protein, is crucial for pyroptosis. Caspase-1 cleaves GSDMD and subsequently induces pyroptosis. In the crosstalk between pyroptosis and necroptosis, necroptosis induces the efflux of potassium ions, which in turn activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induce pyroptosis32–35 (Figure 1).

View this table:
Table 1

Differences among apoptosis, pyroptosis, necroptosis, and PANoptosis

Figure 1
Figure 1

Crosstalk among apoptosis, pyroptosis, and necroptosis. The PANoptosome components, such as Caspase-8 and Caspase-1, engage in crosstalk with other components and consequently modulate the execution of various branches of PANoptosis. ① Some pathogens or stimuli induce Caspase-8 activation and induce apoptosis (pathway marked in purple). In contrast, caspase-8 cleaves and inactivates RIPK1 and RIPK3, 2 key proteins mediating the necroptotic pathway. ② When some pathogens or stimuli induce caspase-8 inactivation, RIPK1 and RIPK3 cleavage by caspase-8 is prevented, and these proteins subsequently bind MLKL, form the necrosome and induce necroptosis (pathway marked in red). ③ In the crosstalk between pyroptosis and apoptosis, Caspase-1 functions as a switch. Caspase-1, a key mediator of pyroptosis, also activates apoptotic pathways in the absence of GSDMD (pathway marked in purple). ④ GSDMD, a pore-forming protein, is crucial in pyroptosis. Caspase-1 cleaves GSDMD, thereby inducing pyroptosis and activating the release of the pro-inflammatory molecules interleukin-1β and interleukin-18, 2 hallmarks of pyroptosis (pathway marked in green). ⑤ In the crosstalk between pyroptosis and necroptosis, necroptosis induces the efflux of potassium ions, which then activate the NLRP3 inflammasome and induce pyroptosis (pathway marked in black). ASC, apoptosis-associated speck-like protein containing a CARD; GSDMD, gasdermin D; IL-1β, interleukin-1β; IL-18, interleukin-18; K+, potassium ions; MLKL, mixed lineage kinase domain like pseudokinase; NLRP3, NLR family pyrin domain containing 3; RIPK1, receptor-interacting serine/threonine kinase 1; RIPK3, receptor-interacting serine/threonine kinase 3; ZBP1, Z-DNA binding protein 1.

The PANoptosome is the core component regulating PANoptosis

The PANoptosome concept was proposed to describe the complex machine driving PANoptosis. The PANoptosome incorporates the inflammasome in pyroptosis, the apoptotic body and related signaling complex in apoptosis, and the dead body in necroptosis36. The composition of the PANoptosome is divided into 3 categories: sensors such as Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), and NLRP3; adapters such as apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and Fas-associated death domain (FADD); and effectors such as RIPK1, RIPK3, Caspase-1, and Caspase-8 (Figure 2). PANoptosome assembly facilitates the integration of various molecules from different cell death pathways, which act as a molecular scaffold that induces signal transduction and crosstalk among these PCDs in response to different stimuli37.

Figure 2
Figure 2

Composition of the PANoptosome. After pathogen infection or other cell homeostasis stimuli, sensors such as ZBP1, AIM2, RIPK1, and NLRP12 are activated and subsequently recruit a variety of partners (such as ASC, CASP-1, and CASP-8, which are indicated by the same color), thus forming PANoptosomes referred to as the ZBP1-PANoptosome, AIM2-PANoptosome, RIPK1-PANoptosome, and NLRP12-PANoptosome. The different PANoptosomes activate downstream effectors such as GSDMD, caspase-3/7, and MLKL, thus inducing pyroptosis, apoptosis, and necroptosis, which together constitute PANoptosis. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a CARD; CASP-1, caspase 1; CASP-3, caspase 3; CASP-7, caspase 7; CASP-8, caspase 8; FADD, Fas associated via death domain; GSDMD, gasdermin D; IL-1β, interleukin-1β; IL-18, interleukin-18; K+, potassium ions; MLKL, mixed lineage kinase domain like pseudokinase; NLRP3, NLR family pyrin domain containing 3; NLRP12, NLR family pyrin domain containing 12; RIPK1, receptor-interacting serine/threonine kinase 1; RIPK3, receptor-interacting serine/threonine kinase 3; ZBP1, Z-DNA binding protein 1.

A variety of PANoptosomes have been identified, including the ZBP1-PANoptosome, AIM2-PANoptosome, RIPK1-PANoptosome, and NLRP12-PANoptosome, which are assembled in response to microbial infections or changes in cell homeostasis (Figure 2). The details of the structure and function of these PANoptosomes have been reviewed recently38–40.

PANoptosis, the TME, and HCC therapy

The TME plays an important role in the progression and metastasis of HCC, because interactions among immune cells, tumor-associated fibroblasts, and hepatic stellate cells in the TME promote inflammation and the progression of HCC41–44. Indeed, the inflammasome, a multiprotein complex that initiates the innate immune response, has been recognized as an important player in HCC progression and a promising therapeutic target45–50. The finding that the inflammasome is a key part of the PANoptosome enables better understanding of the roles of PANoptosis in the regulation of the HCC TME and its potential in HCC immunotherapy.

Necroptosis is an inflammatory programmed cell death that facilitates immune cell infiltration in the TME by inducing the release of inflammatory cytokines and contributes to antitumor immunity51. Necroptosis also facilitates dendritic cell maturation and increases the antitumor potential of CD8 + T cells52. PANoptosis exhibits characteristics of immunogenic cell death and release of proinflammatory cytokines such as IL-1B and IL-18, thereby facilitating immune cell infiltration into the TME53. Natural killer (NK) cells, as part of the innate immune system, recognize and selectively kill tumor cells through surface receptors. NK cells promote a favorable microenvironment for the antigen-specific T-cell immune response, and directly kill cancer cells through a variety of mechanisms including PANoptosis54. Notably, Shi et al.55 have constructed a PANoptosis related gene model of HCC, and analyzed tumor-infiltrating immune cells. The abundance of NK cells in TME in the high-PAN score group highlighted the role of NK cells in PANoptosis in the HCC TME.

HCC therapy is notoriously difficult, because the TME of HCC actively suppresses the immune system and allows HCC cells to evade immune destruction56,57. Therefore, PANoptosis may be used to overcome the immunosuppressive TME of HCC. PANoptosis reprograms the immunosuppressive TME and enhances innate immune responses. PANoptosis promotes dendritic cell maturation and macrophage polarization via the release of damage-associated molecular patterns. Consequently, the release of cytokines triggers inflammatory cell death58. Targeting the PANoptotic cell death pathway not only helps counteract immune evasion but also facilitates a positive feedback loop of immune activation. Therefore, resistance in refractory tumors such as HCC can be overcome.

PANoptosis markedly boosts tumor-specific immunity and is positively associated with the infiltration of a range of immune cells including CD4 + T cells, CD8 + T cells, and NK cells within the TME59,60. Furthermore, immune checkpoint molecules such as CCL2, CD274, CD4, CXCR4, and LAG3 positively correlate with the PANoptotic signature53. Therefore, PANoptosis exerts positive effects in antitumor immunity by promoting immune cell infiltration, upregulating immune checkpoint molecules, and boosting tumor immunogenicity. Unfortunately, few studies have explored the role of PANoptosis in HCC immunotherapy to date. Further investigation of the association between TME of HCC and PANoptosis would aid in the development of novel strategies for HCC immunotherapy. Interestingly, a very recent study using a consensus clustering approach based on TCGA-LIHC data has identified PANoptosis genes associated with the TME of HCC61. Therefore, we believe that detailed dissection of the interplay between PANoptosis and various components in the TME of HCC would reveal therapeutic and prognostic potential for patients with HCC. On the basis of the regulatory role of PANoptosis in the TME, further exploration of its application in predicting treatment response and prognosis in HCC will be highly important.

Application of the PANoptosis signature in predicting HCC therapy response and prognosis

Given the emerging role of PANoptosis in HCC progression, researchers have used bioinformatics tools and online databases to explore the PANoptosis signature of HCC to predict HCC therapy response and prognosis. Liu et al.62 have used single-cell sequencing (scRNA-seq) to categorize patients with HCC into low- and high-PANoptosis groups with diverse biogenic and pharmacotherapy heterogeneity. The PANoptosis index derived from machine learning provides a succinct framework for predicting outcomes and deciphering the immunological ecology hallmarks of patients with HCC. Other groups have identified PANoptosis-associated differentially expressed genes in HCC (named HPAN_DEGs) or PANoptosis-associated genes in HCC (named PANRGs or PRGs by various groups), and constructed a PANoptosis signature to profile the TME landscape of HCC, predict responses to chemotherapy and immunotherapy, and evaluate HCC prognosis55,63–70. Most recently, Wang et al.71 have explored the role of PANoptosis-associated long non-coding RNAs (lncRNAs) in HCC and developed the first PANoptosis-associated lncRNA based risk index in HCC to assess prognosis, the TME, and response to immunotherapy. Another study has explored HCC related PANoptosis-associated lncRNAs (PRLs) and established HCC-associated PRL scores through WGCNA, LASSO analysis, and multivariate Cox assessment. The relationships of the PRL score with immune infiltration and drug sensitivity were further analyzed to evaluate the clinical value of the PRL score-based prognosis model72. Together, these studies have provided new evidence of the roles of PANoptosis-associated lncRNAs in HCC. In summary, PANoptosis signatures consisting of differential genes, RNAs, and proteins might provide novel biomarkers for HCC prognosis.

Use of PANoptosis in HCC therapy

Because PANoptosis is an inflammatory PCD pathway, it has promise in achieving killing of HCC cells. The activation of several PCD pathways such as apoptosis, pyroptosis, and necroptosis has been proposed as a therapeutic strategy for HCC73–75. Recently, Wang et al.76 have reported that deoxyribonuclease 1 like 3 (DNASE1L3) facilitates the generation of double-strand deoxyribonucleic acid breaks and activates the AIM2 PANoptosome during sorafenib-induced HCC cell death. Moreover, DNASE1L3 induced PANoptosis boosts antitumor immunity in the TME and enhances the efficacy of combined sorafenib chemotherapy and PD-1 targeted immunotherapy. Therefore, DNASE1L3 is a promising predictive biomarker and target for HCC therapy. Wei et al.77 have designed a Bi2Sn2O7 nanozyme with ultrasound-magnified multienzyme-mimicking properties as a PANoptosis inducer and shown that triggering PANoptosis activation inhibits lung metastasis in HCC, thus opening a novel avenue for HCC therapy. In detail, Bi2Sn2O7 destroys the mitochondrial function of HCC cells and enhances intracellular accumulation of reactive oxygen species, thus leading to PANoptosis activation. Moreover, the inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency of Bi2Sn2O777. In summary, PANoptosis signatures can be used to personalize HCC treatment by predicting patient response and tailoring therapies accordingly, and the development of targeted therapies that modulate PANoptosis pathways is a promising strategy for HCC therapy.

Conclusions and perspectives

PANoptosis is a newly discovered cell death pathway characterized by the incorporation of pyroptosis, apoptosis, and necrosis. PANoptosis is a complex process that is not completely understood but has been implicated in a wide range of diseases including HCC. Current studies on PANoptosis and HCC remain very limited, but are expected to expand, given the important roles of PANoptosis in HCC progression, TME regulation, and the therapy response.

Current studies on PANoptosis and HCC have focused primarily on the definition of the PANoptosis signature55,62–72. The selection of databases in these studies was not uniform and might present challenges for future studies. The development of PANoptosis inducer drugs, particularly nanomedicine, might bring hope in increasing the efficacy of traditional chemotherapy and new immunotherapies77–79.

Several areas for future investigations should be highlighted. First, the poor prognosis of HCC is due partially to the niche of cancer stem cells, which promote HCC recurrence and metastasis80,81. Inducing PANoptosis of stem cells of HCC is a promising approach to HCC eradication. Second, the prediction of an HCC prognosis based on the PANoptosis signature alone might not be accurate, and combination with other parameters such as HCC angiogenesis should be considered in future studies to construct better prognostic models82–84. Third, with better understanding of holistic tumor ecosystems through the lens of genomics85, PANoptosis related proteins, genes, and RNAs should easily be identifiable in the context of HCC and the HCC related TME, thus achieving breakthroughs in HCC diagnosis, prognostication, and therapy86 (Figure 3).

Figure 3
Figure 3

Implications of the PANoptosis concept in HCC. The development of the PANoptosis concept and the exploration of PANoptosome related proteins, genes, and RNAs in HCC samples are expected to provide powerful strategies for HCC diagnosis, prognostication, and therapy. PANoptosis-associated molecular markers may provide a basis for early diagnosis, prognosis prediction, and personalized treatment of HCC. HCC, hepatocellular carcinoma.

Furthermore, several unresolved questions should be addressed in future studies. For example, how to ensure tissue-specific regulation of PANoptosis in HCC will be important in increasing therapy efficacy and minimizing adverse effects. The use of an HCC specific promoter to drive tissue-specific expression of PANoptosis related genes and proteins should help overcome off-target effects in therapy.

In conclusion, PANoptosis has emerged as a hotspot in cancer research, and the prospects of harnessing PANoptosis for HCC treatment are substantial. Taking advantage of the PANoptosis concept is expected to provide powerful strategies for HCC diagnosis and treatment (Figure 4). Moreover, the integration of novel trends such as machine learning based on artificial intelligence should aid in the development of PANoptosis related diagnosis and prognosis models for HCC, and optimization of the design of PANoptosis targeting drugs87,88. The next major challenges will be to translate diagnostic, prognostic, and therapeutic models into clinical trials, on the basis of understanding of the roles and mechanisms of PANoptosis in HCC. Patients with HCC may be recruited to validate the diagnostic and prognostic models based on PANoptosis related biomarkers. Moreover, PANoptosis targeting drugs may be administered to patients with late-stage HCC for individualized therapy (Figure 4). We are optimistic that these endeavors will greatly benefit patients with HCC in the coming years.

Figure 4
Figure 4

PANoptosis signatures of HCC and the design of PANoptosis inducing drugs for individualized HCC therapy. Various approaches such as single cell sequencing, proteomics analysis, screening of differentially expressed genes and differential lncRNAs have been used to analyze HCC samples and construct PANoptosis signatures of HCC. From HCC PANoptosis signatures, prognostic markers can be identified to classify patients with HCC into groups and predict their responses to chemotherapy and immunotherapy. Furthermore, therapeutic targets including mRNAs, proteins, and lncRNAs can be identified to design nanoparticles such as Bi2Sn2O7. These specially designed drugs could activate the PANoptosome and induce PANoptosis, thus achieving individualized HCC therapy. HCC, hepatocellular carcinoma.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Yang Ke, Zhiwei Li.

Collected the data: Jie Xiang, Yukai Li, Shengmin Mei, Zhiyan Ou, Li Wang.

Contributed data or analysis tools: Yang Ke, Zhiwei Li.

Performed the analysis: Jie Xiang, Yukai Li, Shengmin Mei, Zhiyan Ou, Li Wang.

Wrote the paper: Jie Xiang, Yukai Li, Shengmin Mei, Zhiyan Ou, Li Wang.

Reviewed and revised the paper: Yang Ke, Zhiwei Li.

  • Received March 30, 2025.
  • Accepted June 18, 2025.

References

  1. 1.↵
    2. Xie D,
    3. Shi J,
    4. Zhou J,
    5. Fan J,
    6. Gao Q.
    Clinical practice guidelines and real-life practice in hepatocellular carcinoma: a Chinese perspective. Clin Mol Hepatol. 2023; 29: 206–16.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Yang J,
    3. Yang Z,
    4. Zeng X,
    5. Yu S,
    6. Gao L,
    7. Jiang Y, et al.
    Benefits and harms of screening for hepatocellular carcinoma in high-risk populations: systematic review and meta-analysis. J Natl Cancer Cent. 2023; 3: 175–85.
    OpenUrlPubMed
  3. 3.↵
    2. Yang T,
    3. Zhang H,
    4. Lau WY,
    5. Shen F,
    6. Wu MC.
    Liver disease in China: a long way to go. Hepatology. 2015; 62: 1640.
    OpenUrl
  4. 4.↵
    2. Chen L,
    3. Ye X,
    4. Yang L,
    5. Zhao J,
    6. You J,
    7. Feng Y.
    Linking fatty liver diseases to hepatocellular carcinoma by hepatic stellate cells. J Natl Cancer Cent. 2024; 4: 25–35.
    OpenUrlPubMed
  5. 5.↵
    2. Hwang SY,
    3. Danpanichkul P,
    4. Agopian V,
    5. Mehta N,
    6. Parikh ND,
    7. Abou-Alfa GK, et al.
    Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol. 2024; 31: S228–54.
    OpenUrlPubMed
  6. 6.↵
    2. Krupa K,
    3. Fudalej M,
    4. Cencelewicz-Lesikow A,
    5. Badowska-Kozakiewicz A,
    6. Czerw A,
    7. Deptała A.
    Current treatment methods in hepatocellular carcinoma. Cancers (Basel). 2024; 16: 4059.
    OpenUrlPubMed
  7. 7.
    2. Li YK,
    3. Wu S,
    4. Wu YS,
    5. Zhang WH,
    6. Wang Y,
    7. Li YH, et al.
    Portal venous and hepatic arterial coefficients predict post-hepatectomy overall and recurrence-free survival in patients with hepatocellular carcinoma: a retrospective study. J Hepatocell Carcinoma. 2024; 11: 1389–402.
    OpenUrlPubMed
  8. 8.
    2. Zhang L,
    3. Li YAN,
    4. Mao J.
    Research progress on natural products against hepatocellular carcinoma. Biocell. 2024; 48: 905–22.
    OpenUrl
  9. 9.↵
    2. Yang B,
    3. Chen K,
    4. Liu X,
    5. Liu W,
    6. Ma Y,
    7. Tian X, et al.
    Advance in tumor immunotherapy: establishing a new paradigm for oncological treatment. Transl Surg Oncol. 2023; 1: 30–43.
    OpenUrl
  10. 10.↵
    2. Hou G,
    3. Chen Y,
    4. Lei H,
    5. Lu S,
    6. Cheng L.
    Nanomaterials-induced PANoptosis: a promising anti-tumor strategy. Angew Chem Int Ed Engl. 2025; 64: e202419649.
  11. 11.↵
    2. Cui Z,
    3. Li Y,
    4. Bi Y,
    5. Li W,
    6. Piao J,
    7. Ren X.
    PANoptosis: a new era for anti-cancer strategies. Life Sci. 2024; 359: 123241.
  12. 12.↵
    2. Wan J,
    3. Zhao J,
    4. Fang X.
    Dynamics of the immune microenvironment and immune cell PANoptosis in colorectal cancer: recent advances and insights. Front Immunol. 2024; 15: 1502257.
  13. 13.
    2. Zhu M,
    3. Liu D,
    4. Liu G,
    5. Zhang M,
    6. Pan F.
    Caspase-linked programmed cell death in prostate cancer: from apoptosis, necroptosis, and pyroptosis to PANoptosis. Biomolecules. 2023; 13: 1715.
    OpenUrlPubMed
  14. 14.
    2. Liu X,
    3. Miao M,
    4. Sun J,
    5. Wu J,
    6. Qin X.
    Panoptosis: a potential new target for programmed cell death in breast cancer treatment and prognosis. Apoptosis. 2024; 29: 277–88.
    OpenUrlPubMed
  15. 15.
    2. Zhang C,
    3. Liu N.
    Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer. Front Immunol. 2022; 13: 920059.
  16. 16.
    2. Cai Y,
    3. Xiao H,
    4. Xue S,
    5. Li P,
    6. Zhan Z,
    7. Lin J, et al.
    Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy. J Exp Clin Cancer Res. 2025; 44: 35.
    OpenUrlPubMed
  17. 17.
    2. Liu G,
    3. Pan LZ,
    4. Chen J,
    5. Ma J.
    Unveiling the role of PANoptosis-related genes in breast cancer: an integrated study by multi-omics analysis and machine learning algorithms. Breast Cancer Res Treat. 2025; 211: 35–50.
    OpenUrlPubMed
  18. 18.
    2. Liang C,
    3. Long Z,
    4. Lei M,
    5. Ding R,
    6. Chen M.
    Integrated genomics reveal potential resistance mechanisms of PANoptosis-associated genes in acute myeloid leukemia. Mol Carcinog. 2025; 64: 801–15.
    OpenUrlPubMed
  19. 19.
    2. Wang Y,
    3. Zhao S,
    4. Du S,
    5. Xia T,
    6. Song L,
    7. Xia M, et al.
    Identification of PANoptosis associated lncRNAs associated with clinical prognosis and immune infiltration microenvironment in colon adenocarcinoma. Discov Oncol. 2025; 16: 83.
    OpenUrlPubMed
  20. 20.
    2. Yang K,
    3. Wang Y,
    4. Jian Y,
    5. Wang B,
    6. Du H,
    7. Xia Y, et al.
    CASP5 associated with PANoptosis promotes tumorigenesis and progression of clear cell renal cell carcinoma. Cancer Cell Int. 2025; 25: 8.
    OpenUrlPubMed
  21. 21.
    2. Wang L,
    3. Lin B,
    4. Wang F,
    5. Dai Z,
    6. Xie G,
    7. Zhang J.
    Exploring PANoptosis in head and neck cancer: a novel approach to cancer therapy. Ecotoxicol Environ Saf. 2025; 289: 117678.
  22. 22.↵
    2. Fu H,
    3. Liu M,
    4. Li H,
    5. Yu L,
    6. Song H,
    7. Chu X, et al.
    Deciphering the prognostic landscape of esophageal adenocarcinoma: a PANoptosis-related gene signature. J Cancer. 2025; 16: 183–200.
    OpenUrlPubMed
  23. 23.↵
    2. Bedoui S,
    3. Herold MJ,
    4. Strasser A.
    Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. 2020; 21: 678–95.
    OpenUrlCrossRefPubMed
  24. 24.↵
    2. Lee E,
    3. Song CH,
    4. Bae SJ,
    5. Ha KT,
    6. Karki R.
    Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis. Exp Mol Med. 2023; 55: 1632–43.
    OpenUrlCrossRefPubMed
  25. 25.↵
    2. Malireddi RKS,
    3. Kesavardhana S,
    4. Kanneganti TD.
    ZBP1 and TAK1: master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis). Front Cell Infect Microbiol. 2019; 9: 406.
    OpenUrlPubMed
  26. 26.↵
    2. Wang Y,
    3. Kanneganti TD.
    From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021; 19: 4641–57.
    OpenUrlCrossRefPubMed
  27. 27.↵
    2. Man SM,
    3. Kanneganti TD.
    Innate immune sensing of cell death in disease and therapeutics. Nat Cell Biol. 2024; 26: 1420–33.
    OpenUrlPubMed
  28. 28.↵
    2. Wong RS.
    Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011; 30: 87.
    OpenUrlCrossRefPubMed
  29. 29.↵
    2. Kovacs SB,
    3. Miao EA.
    Gasdermins: effectors of pyroptosis. Trends Cell Biol. 2017; 27: 673–84.
    OpenUrlCrossRefPubMed
  30. 30.↵
    2. Galluzzi L,
    3. Kepp O,
    4. Chan FK,
    5. Kroemer G.
    Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol. 2017; 12: 103–30.
    OpenUrlCrossRefPubMed
  31. 31.↵
    2. Jia Y,
    3. Liu Y,
    4. Zuo Y,
    5. Zhang J,
    6. Li Y,
    7. Liu X, et al.
    The potential therapeutic prospect of PANoptosis in heart failure. J Inflamm Res. 2024; 17: 9147–68.
    OpenUrlPubMed
  32. 32.↵
    2. Zhang M,
    3. Lan H,
    4. Jiang M,
    5. Yang M,
    6. Chen H,
    7. Peng S, et al.
    NLRP3 inflammasome mediates pyroptosis of alveolar macrophages to induce radiation lung injury. J Hazard Mater. 2025; 484: 136740.
  33. 33.
    2. Mou Y,
    3. Liao W,
    4. Liang Y,
    5. Li Y,
    6. Zhao M,
    7. Guo Y, et al.
    Environmental pollutants induce NLRP3 inflammasome activation and pyroptosis: roles and mechanisms in various diseases. Sci Total Environ. 2023; 900: 165851.
  34. 34.
    2. Zhao P,
    3. Zhu J,
    4. Bai L,
    5. Ma W,
    6. Li F,
    7. Zhang C, et al.
    Neutrophil extracellular traps induce pyroptosis of pulmonary microvascular endothelial cells by activating the NLRP3 inflammasome. Clin Exp Immunol. 2024; 217: 89–98.
    OpenUrlPubMed
  35. 35.↵
    2. Hoblos H,
    3. Cawthorne W,
    4. Samson AL,
    5. Murphy JM.
    Protein shapeshifting in necroptotic cell death signaling. Trends Biochem Sci. 2025; 50: 92–105.
    OpenUrlPubMed
  36. 36.↵
    2. Christgen S,
    3. Zheng M,
    4. Kesavardhana S,
    5. Karki R,
    6. Malireddi RKS,
    7. Banoth B, et al.
    Identification of the PANoptosome: a molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis). Front Cell Infect Microbiol. 2020; 10: 237.
    OpenUrlPubMed
  37. 37.↵
    2. Samir P,
    3. Malireddi RKS,
    4. Kanneganti TD.
    The PANoptosome: a deadly protein complex driving pyroptosis, apoptosis, and necroptosis (PANoptosis). Front Cell Infect Microbiol. 2020; 10: 238.
    OpenUrlPubMed
  38. 38.↵
    2. Nadella V,
    3. Kanneganti TD.
    Inflammasomes and their role in PANoptosomes. Curr Opin Immunol. 2024; 91: 102489.
  39. 39.
    2. Sun X,
    3. Yang Y,
    4. Meng X,
    5. Li J,
    6. Liu X,
    7. Liu H.
    PANoptosis: mechanisms, biology, and role in disease. Immunol Rev. 2024; 321: 246–62.
    OpenUrlCrossRefPubMed
  40. 40.↵
    2. Karki R,
    3. Kanneganti TD.
    PANoptosome signaling and therapeutic implications in infection: central role for ZBP1 to activate the inflammasome and PANoptosis. Curr Opin Immunol. 2023; 83: 102348.
  41. 41.↵
    2. Meng L,
    3. Zheng Y,
    4. Liu H,
    5. Fan D.
    The tumor microenvironment: a key player in multidrug resistance in cancer. Oncologie. 2024; 26: 41–58.
    OpenUrl
  42. 42.
    2. Fu X,
    3. Zhang Y,
    4. Luo Q,
    5. Ju Y,
    6. Song G.
    Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer. Cancer Biol Med. 2023; 20: 816–29.
    OpenUrlAbstract/FREE Full Text
  43. 43.
    2. Chen S,
    3. Du Y,
    4. Guan XY,
    5. Yan Q.
    The current status of tumor microenvironment and cancer stem cells in sorafenib resistance of hepatocellular carcinoma. Front Oncol. 2023; 13: 1204513.
  44. 44.↵
    2. Yao C,
    3. Wu S,
    4. Kong J,
    5. Sun Y,
    6. Bai Y,
    7. Zhu R, et al.
    Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies. Cancer Biol Med. 2023; 20: 25–43.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    2. Arrè V,
    3. Negro R,
    4. Giannelli G.
    The role of inflammasomes in hepatocellular carcinoma: mechanisms and therapeutic insights. Ann Hepatol. 2024; 30: 101772.
  46. 46.
    2. Tutusaus A,
    3. Sanduzzi-Zamparelli M,
    4. Boix L,
    5. Rider P,
    6. Subías S,
    7. García de Frutos P, et al.
    Induction of the inflammasome pathway by tyrosine kinase inhibitors provides an actionable therapeutic target for hepatocellular carcinoma. Cancers (Basel). 2024; 16: 1491.
    OpenUrlPubMed
  47. 47.
    2. Ramos-Tovar E,
    3. Muriel P.
    NLRP3 inflammasome in hepatic diseases: a pharmacological target. Biochem Pharmacol. 2023; 217: 115861.
  48. 48.
    2. Li Z,
    3. Yang Z,
    4. Zhu Y,
    5. Fu C,
    6. Li N,
    7. Peng F.
    Sorcin regulate pyroptosis by interacting with NLRP3 inflammasomes to facilitate the progression of hepatocellular carcinoma. Cell Death Dis. 2023; 14: 678.
    OpenUrlPubMed
  49. 49.
    2. Dai B,
    3. Cao H,
    4. Hu Y,
    5. Gong Z,
    6. Huang X,
    7. Chen Y, et al.
    Role of NLRP3 inflammasome activation in HCC cell progression. Heliyon. 2023; 9: e19542.
  50. 50.↵
    2. He F,
    3. He Z,
    4. Wang C.
    A novel role of AIM2 inflammasome-mediated pyroptosis in radiofrequency ablation of hepatocellular carcinoma. Ann Hepatol. 2024; 29: 101532.
  51. 51.↵
    2. Zhang Y,
    3. Yi S,
    4. Luan M.
    Advances in non-apoptotic regulated cell death: implications for malignant tumor treatment. Front Oncol. 2025; 15: 1519119.
  52. 52.↵
    2. Yatim N,
    3. Jusforgues-Saklani H,
    4. Orozco S,
    5. Schulz O,
    6. Barreira da Silva R,
    7. Reis e Sousa C, et al.
    RIPK1 and NF-KB signaling in dying cells determines cross-priming of CD8⁺ T cells. Science. 2015; 350: 328–34.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    2. Yi X,
    3. Li J,
    4. Zheng X,
    5. Xu H,
    6. Liao D,
    7. Zhang T, et al.
    Construction of PANoptosis signature: novel target discovery for prostate cancer immunotherapy. Mol Ther Nucleic Acids. 2023; 33: 376–90.
    OpenUrlPubMed
  54. 54.↵
    2. Guillerey C,
    3. Huntington ND,
    4. Smyth MJ.
    Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016; 17: 1025–36.
    OpenUrlCrossRefPubMed
  55. 55.↵
    2. Shi X,
    3. Gao X,
    4. Liu W,
    5. Tang X,
    6. Liu J,
    7. Pan D, et al.
    Construction of the panoptosis-related gene model and characterization of tumor microenvironment infiltration in hepatocellular carcinoma. Oncol Res. 2023; 31: 569–90.
    OpenUrlPubMed
  56. 56.↵
    2. Bai Y,
    3. Chen D,
    4. Cheng C,
    5. Li Z,
    6. Chi H,
    7. Zhang Y, et al.
    Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing. Front Immunol. 2022; 13: 950536.
  57. 57.↵
    2. Lin X,
    3. Tian C,
    4. Pan F,
    5. Wang R.
    A novel immune-associated prognostic signature based on the immune cell infiltration analysis for hepatocellular carcinoma. Oncologie. 2024; 26: 91–103.
    OpenUrl
  58. 58.↵
    2. Zhou L,
    3. Lyu J,
    4. Liu F,
    5. Su Y,
    6. Feng L,
    7. Zhang X.
    Immunogenic PANoptosis-initiated cancer sono-immune reediting nanotherapy by iteratively boosting cancer immunity cycle. Adv Mater. 2024; 36: e2305361.
  59. 59.↵
    2. Liu Z,
    3. Sun L,
    4. Peng X,
    5. Zhu J,
    6. Wu C,
    7. Zhu W, et al.
    PANoptosis subtypes predict prognosis and immune efficacy in gastric cancer. Apoptosis. 2024; 29: 799–815.
    OpenUrlPubMed
  60. 60.↵
    2. Hu Q,
    3. Wang R,
    4. Zhang J,
    5. Xue Q,
    6. Ding B.
    Tumor-associated neutrophils upregulate PANoptosis to foster an immunosuppressive microenvironment of non-small cell lung cancer. Cancer Immunol Immunother. 2023; 72: 4293–308.
    OpenUrlPubMed
  61. 61.↵
    2. Wang X,
    3. Qu L,
    4. Wen Z,
    5. Wu Z,
    6. Xue Y,
    7. Yang X, et al.
    PANoptosis-related genes in the prognosis and immune landscape of hepatocellular carcinoma. Immunol Res. 2025; 73: 51.
    OpenUrlPubMed
  62. 62.↵
    2. Liu L,
    3. Zhou Z,
    4. Xie C,
    5. Hu L.
    Combination of bulk RNA and single-cell sequencing unveils PANoptosis-related immunological ecology hallmarks and classification for clinical decision-making in hepatocellular carcinoma. Sci Rep. 2024; 14: 22517.
  63. 63.↵
    2. Xiong X,
    3. Song Q,
    4. Jing M,
    5. Yan W.
    Identification of PANoptosis-based prognostic signature for predicting efficacy of immunotherapy and chemotherapy in hepatocellular carcinoma. Genet Res (Camb). 2023; 2023: 6879022.
  64. 64.
    2. Peng F,
    3. Zhu F,
    4. Cao B,
    5. Peng L.
    Multidimensional analysis of PANoptosis-related molecule CASP8: prognostic significance, immune microenvironment effect, and therapeutic implications in hepatocellular carcinoma. Genet Res (Camb). 2023; 2023: 2406193.
  65. 65.
    2. Ren H,
    3. Kang N,
    4. Yin S,
    5. Xu C,
    6. Qu T,
    7. Dai D.
    Characteristic of molecular subtypes based on PANoptosis-related genes and experimental verification of hepatocellular carcinoma. Aging (Albany NY). 2023; 15: 4159–81.
    OpenUrlPubMed
  66. 66.
    2. Ouyang G,
    3. Li Q,
    4. Wei Y,
    5. Dai W,
    6. Deng H,
    7. Liu Y, et al.
    Identification of PANoptosis-related subtypes, construction of a prognosis signature, and tumor microenvironment landscape of hepatocellular carcinoma using bioinformatic analysis and experimental verification. Front Immunol. 2024; 15: 1323199.
  67. 67.
    2. Zhang Z,
    3. Zhang F,
    4. Pang P,
    5. Li Y,
    6. Chen X,
    7. Sun S, et al.
    Identification of PANoptosis-relevant subgroups to evaluate the prognosis and immune landscape of patients with liver hepatocellular carcinoma. Front Cell Dev Biol. 2023; 11: 1210456.
  68. 68.
    2. Wei Y,
    3. Lan C,
    4. Yang C,
    5. Liao X,
    6. Zhou X,
    7. Huang X, et al.
    Robust analysis of a novel PANoptosis-related prognostic gene signature model for hepatocellular carcinoma immune infiltration and therapeutic response. Sci Rep. 2023; 13: 14519.
  69. 69.
    2. Zhu J,
    3. Huang Q,
    4. Peng X,
    5. Luo C,
    6. Liu Z,
    7. Liu D, et al.
    Identification of molecular subtypes based on PANnoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma. Front Immunol. 2023; 14: 1218661.
  70. 70.↵
    2. Song F,
    3. Wang CG,
    4. Mao JZ,
    5. Wang TL,
    6. Liang XL,
    7. Hu CW, et al.
    PANoptosis-based molecular subtyping and HPAN-index predicts therapeutic response and survival in hepatocellular carcinoma. Front Immunol. 2023; 14: 1197152.
  71. 71.↵
    2. Wang L,
    3. Wan P,
    4. Xu Z.
    A novel PANoptosis-related long non-coding RNA index to predict prognosis, immune microenvironment and personalised treatment in hepatocellular carcinoma. Aging (Albany NY). 2024; 16: 2410–37.
    OpenUrlPubMed
  72. 72.↵
    2. Shu Q,
    3. Zhu J,
    4. Mo J,
    5. Wei X,
    6. Zhu Z,
    7. Chen X, et al.
    Identification and validation of PANoptosis-related LncRNAs prognosis system in hepatocellular carcinoma. Sci Rep. 2025; 15: 6030.
    OpenUrlPubMed
  73. 73.↵
    2. Karati D,
    3. Kumar D.
    Molecular insight into the apoptotic mechanism of cancer cells: an explicative review. Curr Mol Pharmacol. 2024; 17: e18761429273223.
  74. 74.
    2. Liu RJ,
    3. Yu XD,
    4. Yan SS,
    5. Guo ZW,
    6. Zao XB,
    7. Zhang YS.
    Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: mechanisms and immunologic landscape (Review). Int J Oncol. 2024; 64: 63.
    OpenUrlPubMed
  75. 75.↵
    2. Wang L,
    3. Wang J,
    4. Shi C,
    5. Wang W,
    6. Wu J.
    ABHD17C represses apoptosis and pyroptosis in hepatocellular carcinoma cells. Biocell. 2024; 48: 1299–310.
    OpenUrl
  76. 76.↵
    2. Wang J,
    3. Chen Y,
    4. Xu Y,
    5. Zhang J,
    6. Yang S,
    7. Zhou Y, et al.
    DNASE1L3-mediated PANoptosis enhances the efficacy of combination therapy for advanced hepatocellular carcinoma. Theranostics. 2024; 14: 6798.
    OpenUrlPubMed
  77. 77.↵
    2. Wei W,
    3. Wang H,
    4. Ren C,
    5. Deng R,
    6. Qin Q,
    7. Ding L, et al.
    Ultrasmall enzyodynamic PANoptosis nano-inducers for ultrasound-amplified hepatocellular carcinoma therapy and lung metastasis inhibition. Adv Mater. 2024; 36: e2409618.
  78. 78.
    2. Sensi B,
    3. Angelico R,
    4. Toti L,
    5. Conte L,
    6. Coppola A,
    7. Tisone G, et al.
    Mechanism, potential, and concerns of immunotherapy for hepatocellular carcinoma and liver transplantation. Curr Mol Pharmacol. 2024; 17: e18761429310703.
  79. 79.↵
    2. Yang D.
    The potential of siglec receptors in cancer immunotherapy. Transl Surg Oncol. 2024; 1: 76–89.
    OpenUrl
  80. 80.↵
    2. Tsui YM,
    3. Tian L,
    4. Lu J,
    5. Ma H,
    6. Ng IO.
    Interplay among extracellular vesicles, cancer stemness and immune regulation in driving hepatocellular carcinoma progression. Cancer Lett. 2024; 597: 217084.
  81. 81.↵
    2. Balaji N,
    3. Kukal S,
    4. Bhat A,
    5. Pradhan N,
    6. Minocha S,
    7. Kumar S.
    A quartet of cancer stem cell niches in hepatocellular carcinoma. Cytokine Growth Factor Rev. 2024; 79: 39–51.
    OpenUrlPubMed
  82. 82.↵
    2. Li J,
    3. Wang QB,
    4. Liang YB,
    5. Chen XM,
    6. Luo WL,
    7. Li YK, et al.
    Tumor-associated lymphatic vessel density is a reliable biomarker for prognosis of esophageal cancer after radical resection: a systemic review and meta-analysis. Front Immunol. 2024; 15: 1453482.
  83. 83.
    2. Zeng Y,
    3. Jiang S,
    4. Lou Z,
    5. Chen L,
    6. Zhang Y,
    7. Pan L, et al.
    Clinical significance of a novel vasculogenic mimicry-based prognostic model in hepatocellular carcinoma. Curr Med Chem. 2024. DOI: 10.2174/0109298673298862240510073543.
    OpenUrlCrossRef
  84. 84.↵
    2. Li J,
    3. Liang YB,
    4. Wang QB,
    5. Li YK,
    6. Chen XM,
    7. Luo WL, et al.
    Tumor-associated lymphatic vessel density is a postoperative prognostic biomarker of hepatobiliary cancers: a systematic review and meta-analysis. Front Immunol. 2024; 15: 1519999.
  85. 85.↵
    2. Wang D,
    3. Liu B,
    4. Zhang Z.
    Accelerating the understanding of cancer biology through the lens of genomics. Cell. 2023; 186: 1755–71.
    OpenUrlCrossRefPubMed
  86. 86.↵
    2. Yang S,
    3. Zou Y,
    4. Zhong C,
    5. Zhou Z,
    6. Peng X,
    7. Tang C.
    Dual role of pyroptosis in liver diseases: mechanisms, implications, and therapeutic perspectives. Front Cell Dev Biol. 2025; 13: 1522206.
  87. 87.↵
    2. Swanson K,
    3. Wu E,
    4. Zhang A,
    5. Alizadeh AA,
    6. Zou J.
    From patterns to patients: advances in clinical machine learning for cancer diagnosis, prognosis, and treatment. Cell. 2023; 186: 1772–91.
    OpenUrlCrossRefPubMed
  88. 88.↵
    2. Harkos C,
    3. Hadjigeorgiou AG,
    4. Voutouri C,
    5. Kumar AS,
    6. Stylianopoulos T,
    7. Jain RK.
    Using mathematical modelling and AI to improve delivery and efficacy of therapies in cancer. Nat Rev Cancer. 2025; 25: 324–40.
    OpenUrlPubMed
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