2.1 Activation and Progression of PANoptosis

PANoptosis is a complex form of programmed cell death that integrates features of pyroptosis, apoptosis, and necroptosis, challenging traditional classification within these categories [17]. This intricate process is triggered by a variety of stimuli, particularly in response to infections or during cellular stress. The innate immune system detects invading pathogens through pathogen-associated molecular patterns (PAMPs), which are unique molecular structures foreign to the body. Concurrently, damage-associated molecular patterns (DAMPs), endogenous molecules released due to cellular damage, also signal the immune response. These signals are recognised by specific sensors that initiate PANoptosis by assembling the PANoptosome complex.

As depicted in Figure 1, under cellular stress or infection, the activation of sensors, such as Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase(RIPK) 1, and nucleotide-binding leucine-rich repeat-containing receptor (NLRP) 12 leads to the formation of a PANoptosome complex. This complex sets off a cascade of events, including the activation of caspases (e.g., Caspase-3/7), the cleavage of gasdermin proteins (e.g., Gasdermin D and Gasdermin E), and the phosphorylation of mixed lineage kinase domain (MLKL). These events ultimately result in the formation of membrane pores and the rupture of the cell membrane. In addition, PANoptosis can be activated by mitochondrial damage and endoplasmic reticulum stress. In the later stages of PANoptosis, this rupture leads to the release of intracellular contents and inflammatory cytokines, thereby initiating an immune response.

The resulting inflammatory reaction is crucial for controlling infections and maintaining tissue homeostasis, thus reinforcing the body's defence mechanisms and preserving cellular balance. The interplay between PANoptosis and immune response underscores the significance of this complex form of cell death in both physiological and pathological contexts. Understanding the activation and regulation of PANoptosis is essential for deciphering its role in disease progression and for developing targeted therapeutic strategies.

2.2 PANoptosome Assembly and Regulation in PANoptosis

In PANoptosis, sensors detect different PAMPs or DAMPs, initiating the assembly of PANoptosomes in a context-dependent manner. This assembly activates pyroptosis, apoptosis, and necroptosis simultaneously through various catalytic effectors, highlighting the PANoptosome complex as the central component of PANoptosis regulation [18]. Four distinct types of PANoptosomes have been identified, the ZBP1 PANoptosome [19, 20], the RIPK1 PANoptosome [21, 22], the AIM2 PANoptosome [23], and the NLRP12 PANoptosome [24], each with its unique sensors and regulators.

The ZBP1 PANoptosome, which assembles in response to IAV infection or NEI and Interferon (IFN) stimulation, includes components, such as ZBP1, apoptosis-associated speck-like protein (ASC), RIPK1, RIPK3, NLRP3, Caspase-1, Caspase-6, and Caspase-8 [20, 25]. The AIM2 PANoptosome forms following HSV1 or Francisella infection, with AIM2 as the sensor, and includes AIM2, Pyrin, ZBP1, ASC, Caspase-1, Caspase-8, RIPK3, RIPK1, and FADD [23]. The RIPK1 PANoptosome assembles in the absence or inhibition of Transforming growth factor-β-activated kinase 1 (TAK1) upon Yersinia infection, consisting of RIPK1, NLRP3, ASC, Caspase-1, RIPK3, FADD, and Caspase-8 [26]. Finally, the NLRP12 PANoptosome assembles in response to heme plus PAMP stimulation, composed of NLRP12, ASC, RIPK3, and Caspase-8 [24, 27].

Each PANoptosome, while uniquely composed, generally consists of three components: (a) Sensors that detect PAMPs or DAMPs, including not only the aforementioned sensors but also others, such as NLRP3 [28], NLR Family CARD domain containing (NLRC) 5 [29], and NLRC4 of the NLR family [30], Pyrin [23]. (b) Adaptors that serve as connecting bridges, with adapter proteins like ASC containing a caspase recruitment domain, facilitating the assembly of the PANoptosome complex [31]. (c) Catalytic effectors or executioners, including RIPK1, RIPK3, and Caspase-1/8 [23, 25], which mediate the downstream signalling events leading to cell death [32].

2.3 Endoplasmic Reticulum Stress in PANoptosis

In addition to the PANoptosome, endoplasmic reticulum stress and mitochondrial damage are also not negligible in the development of PANoptosis. Endoplasmic reticulum stress is a response mechanism triggered by endoplasmic reticulum dysfunction, which is usually caused by a variety of factors, such as hypoxia, nutritional deficiencies, pathogen infections, and responses to certain drugs, and leads to the accumulation of unfolded proteins. When the endoplasmic reticulum senses abnormally folded proteins, it initiates the unfolded protein response in an attempt to restore endoplasmic reticulum function and avoid cell death. However, if endoplasmic reticulum stress is too severe to be effectively regulated, cell death can result [33]. Endoplasmic reticulum stress-induced cellular injury and metabolic disturbances can activate signalling pathways associated with PANoptosis [34]. These signalling pathways may involve the release of endogenous molecules that activate sensors required for PANoptosis for cell death [35]. In ALF, the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid weakened the promotion effect of the deacetylated mechanism of deacetylated malate dehydrogenase 1 (MDH1) K118 and isocitrate dehydrogenase 1 (IDH1) K93 on PANoptosis [36]. The relationship between endoplasmic reticulum stress and pan-apoptosis exhibits interactive and dependent properties. By modulating the endoplasmic reticulum stress response, cells determine different modes of death in response to dysfunctions and pathological states. It is important to consider the interrelationship between the two when studying the mechanisms of PANoptosis and its role in disease.

2.4 Mitochondrial Damage in PANoptosis

Mitochondria are essential organelles within the cell, with a broad range of functions that encompass energy production, metabolic regulation, reactive oxygen species (ROS) signalling, calcium homeostasis, and various aspects of cell death mechanisms. They also serve as the hub of the intrinsic apoptotic pathway induced by a variety of stimuli [37]. Mitochondrial damage can lead to metabolic dysregulation, which in turn can trigger cellular stress responses that provide the inducing conditions for PANoptosis. Zhang et al. discovered that when damaged mitochondria are released into the circulation, specific mitochondrial components are recognised as PAMPs by pattern recognition receptors of the innate immune system, thereby driving inflammatory responses [38]. Mitochondrial damage results in the release of intrinsic pro-apoptotic factors, such as cytochrome c (Cyt c) from the mitochondria into the cytoplasm; these factors can activate caspases, enhance apoptotic signalling, and interact with PANoptosis signalling pathways, increasing the risk of PANoptosis [39]. Additionally, mitochondrial damage can trigger inflammatory responses within the cell, leading to the release of DAMPs [40], which can activate various modes of cell death, including apoptosis and pyroptosis [41]. When mitochondria are severely damaged, they may initiate the PANoptosis pathway rather than being limited to a single death program. PANoptosis integrates these diverse death signals, providing a mechanism for cells to cope with extreme stress. Overall, mitochondrial damage is closely related to PANoptosis through its impact on cellular energy metabolism, the release of pro-apoptotic factors, and inflammatory responses. A deeper understanding of the relationship between mitochondrial damage and PANoptosis can help reveal the mechanisms of cell death and their roles in various diseases, offering potential targets for treatment.

3.1 Caspase-8 in PANoptosis

Caspase-8 is the central regulatory molecule of PANoptosis, and its activation is a key step in the PANoptotic pathway [42]. Under certain conditions, such as the loss of function of TAK1 kinase, Caspase-8 can promote the assembly of PANoptosomes, leading to the occurrence of PANoptosis [16, 43]. The role of Caspase-8 in PANoptosis is not only involved in the execution of cell death but may also be involved in the crosstalk and regulation between cell death pathways. Under specific conditions, such as viral infection, Caspase-8 can be activated through various receptors (including death receptors). Once activated, Caspase-8 initiates a cascade of events leading to the activation of other caspases and promoting cell death. As a key protease, Caspase-8 mediates apoptosis, but it is not only responsible for initiating the apoptotic process; it can also activate other cell death pathways [44].

When Caspase-8 is enzymatically active, it primarily drives apoptosis, a process that does not cause tissue damage and is essential for the removal of unwanted cells, such as infected or senescent cells. However, when Caspase-8 lacks enzymatic activity, it can lead to embryonic lethality and inflammatory tissue destruction by inducing necroptosis and pyroptosis [45, 46]. In the context of PANoptosis, the enzymatic activity of Caspase-8 is crucial for inhibiting pyroptosis, a highly inflammatory form of cell death that is activated in response to microbial pathogens and is crucial for enhancing antimicrobial immunity [47]. Interestingly, when necroptosis is blocked, enzymatically inactive Caspase-8 can act as a protein scaffold to form an inflammasome complex, which ultimately leads to pyroptosis [48]. Moreover, the study by Hamid Kashkar's team revealed that the expression of enzymatically inactive Caspase-8 induces necroptosis and pyroptosis, causing embryonic lethality in mice [42]. This indicates that Caspase-8, regardless of its enzymatic activity, plays a significant role in the regulation of cell death mechanisms. In summary, the function of Caspase-8 is multifaceted; with enzymatic activity, it drives apoptosis, while without enzymatic activity, it can induce both necroptosis and pyroptosis, highlighting its role as a critical regulatory node in cell death pathways.

3.2 Gasdermin Proteins in PANoptosis

Gasdermin proteins are a family of pore-forming proteins capable of mediating a highly inflammatory form of cell death known as pyroptosis, which is a component of PANoptosis. Gasdermin proteins typically require cleavage by inflammasomes or caspase proteases for activation. For instance, Gasdermin D (GSDMD) can be cleaved by Caspase-1 or Caspase-11, releasing its N-terminal domain, which oligomerizes on the cell membrane to form pores, leading to cell death and the release of inflammatory cytokines [49]. The activated N-terminal domain of Gasdermin proteins oligomerizes on the cell membrane, forming pores that compromise the integrity of the cell membrane, a characteristic event of pyroptosis [50, 51]. The pore formation mediated by Gasdermin leads to the release of cellular contents that can act as DAMPs, activating inflammatory responses [52]. In PANoptosis, pyroptosis mediated by Gasdermin proteins may act in concert with apoptosis and necroptosis to collectively promote cell death [53]. The activity of Gasdermin proteins is tightly regulated. The activation and function of Gasdermin proteins are regulated by various mechanisms, including post-translational modifications and protein–protein interactions. In addition, their activation and function are crucial for controlling cell death and inflammatory responses [54]. Overall, Gasdermin proteins contribute to PANoptosis by mediating membrane pore formation and promoting inflammatory responses, synergizing with other cell death mechanisms to participate in the cell death process.

3.3 MLKL in PANoptosis

MLKL plays a crucial role in the molecular mechanisms of PANoptosis, particularly in mediating necroptosis, which is one of the components of PANoptosis. MLKL, identified as a downstream target of RIPK3, acts as the executioner of necroptosis [55]. MLKL is activated through phosphorylation by RIPK3, which is triggered by various stimuli, including death receptor ligands and PAMPs. Upon phosphorylation, MLKL undergoes a conformational change that leads to its translocation from the cytosol to cellular membranes, where it induces membrane permeabilisation. The translocated MLKL causes loss of membrane integrity, resulting in the release of cellular contents and inflammatory responses characteristic of necroptosis [56]. MLKL contributes to the cell death pathway through interactions with other components of the apoptotic, pyroptotic, and necroptotic pathways [57-59]. The role of MLKL in PANoptosis is many-sided, and its activation and function are tightly regulated, making it a potential therapeutic target in diseases where PANoptosis plays a significant role.

4.1 Activators of PANoptosis

PANoptosis can be triggered or amplified by various activators, which may be endogenous or exogenous in nature. Endogenous activators include intracellular molecules or signals, such as PAMPs like bacterial lipopolysaccharide (LPS) and viral RNA, which are recognised by pattern recognition receptors to initiate PANoptosis [60]. Transcription factor Interferon regulatory factor 1 (IRF1) can promote PANoptosis by regulating ZBP1, thus playing a role in cell death regulation in diseases like influenza virus infection and colorectal cancer [61, 62]. In addition, some pro-inflammatory factors, including tumour necrosis factor (TNF)-α, IFN-γ can also promote cell death and may induce PANoptosis under specific conditions [63]. Pro-inflammatory factors can activate the JAK/STAT1/IRF1 axis, inducing nitric oxide (NO) production and caspase-8/FADD-mediated PANoptosis, particularly evident in SARS-CoV-2 infection [63]. DAMPs, such as high mobility group box 1 (HMGB1) and heat shock proteins, are released during cell injury or death and also contribute to the activation of PANoptosis [15, 64]. Y-box-binding protein 1 (YBX1) is a multifunctional protein in the RBP family that promotes ZBP1 expression by stabilising the Zbp1 mRNA, thereby exacerbating ZBP1-mediated PANoptosis [65]. Moreover, eukaryotic translation initiation factor 2 alpha kinase 2 can activate PANoptosis by inducing AIM2 upregulation [66]. The activation of death receptors like Fas and TNF receptor 1 can also initiate PANoptosis, either through caspase-dependent or -independent pathways [67, 68].

Exogenous activators encompass chemotherapeutic agents, antiviral drugs, environmental factors, and certain chemicals that induce cellular stress [69]. Viral infections, particularly those that activate the RIPK1/RIPK3/MLKL pathway, can directly trigger PANoptosis [23, 70]. Some chemical substances that induce cellular stress may facilitate the signalling pathways associated with PANoptosis. For instance, specific activators of signalling pathways, such as NF-κB, JNK, and p38 MAPK, may indirectly promote PANoptosis by influencing the expression of PANoptosis-related genes and modulating inflammatory and immune responses [71-73]. Diamidobenzimidazole acts as a stimulator of interferon genes pathway agonist, leading to PANoptosis through IFN-dependent mechanisms accompanied by acute lung inflammation and inflammatory cytokine production [74]. Genetic mutations affecting PANoptosis-related proteins may lead to abnormal activation of PANoptosis and immune activation through T-cell receptors or B-cell receptors can promote PANoptosis in certain contexts. The activation of PANoptosis is a multifaceted process involving numerous signalling pathways and molecular interactions, and the specific activators may vary depending on cell type and environmental conditions. Understanding these activators is crucial for elucidating the role of PANoptosis in diseases and for developing novel therapeutic strategies.

4.2 Inhibitors of PANoptosis

Many factors can activate PANoptosis, yet at the current stage, no specific inhibitor is widely recognised. The occurrence of PANoptosis is closely related to apoptosis, pyroptosis, and necroptosis, and many factors play an important role in its progression. Therefore, the inhibitors related to these factors can be considered as references. Inhibitors of PANoptosis comprise various enzymes, compounds, and proteins that restrict this form of cell death through different mechanisms. ZBP1 is a key sensor in PANoptosis, and its inhibitors may suppress PANoptosis by blocking the assembly of the ZBP1-PANoptosome. Karki et al. showed that adenosine deaminase acting on RNA-1 interacts with the Zα2 domain of ZBP1 to inhibit its interaction with RIPK3, thus suppressing PANoptosis and contributing to tumorigenesis in colorectal cancer and melanoma [75]. Tripartite motif containing 56 (TRIM 56) is an endogenous inhibitor of YBX1. In spinal cord injury, the interaction between TRIM 56 and YBX1 is a key molecular event that promotes the degradation of YBX1, thereby suppressing ZBP1 expression and mitigating PANoptosis, improving spinal cord injury [65]. Apart from ZBP1, the absence of other key factors of PANoptosis can also inhibit PANoptosis. Studies have shown that deleting the core components of the PANoptosome, Caspase-8, and RIPK3, can inhibit PANoptosis [76]. It can be reasonably speculated that knocking out key regulatory factors of PANoptosis through gene-editing technologies, such as CRISPR/Cas9, can directly suppress PANoptosis.

It was also found that some plant extracts also have an inhibitory effect on PANoptosis. Baicalin inhibits PANoptosis in macrophages by blocking the formation of mitochondrial Z-DNA and the assembly of the ZBP1-PANoptosome, thereby protecting against inflammatory diseases [16]. Cucurbitacin E can inhibit cyclin-dependent kinases1 through interaction with the PANoptosome in a ZBP1-dependent manner [77]. In addition, it was found that NO was identified as a novel upstream signalling molecule for PANoptosis [63]. Echinacea polyphenols may inhibit pan-cellular apoptosis by decreasing inducible NO synthase activity and NO production [78]. Other inhibitors include cysteine desulphurase, which blocks PANoptosis during cisplatin treatment in a phosphorylation-dependent manner [79]. Dickkopf-related protein 1 inhibits PANoptosis by blocking molecules like GSDMD and caspase-3 [80]. FUN14 domain containing 1 interacted with mitochondrial Tu translation elongation factor to prevent cytoplasmic mitochondrial DNA release and PANoptosom [81]. Melatonin can inhibit PANoptosis by reducing the expression of various pro-inflammatory factors, such as NLRP3 and ASC [82]. 3,4-Methylenedioxy-β-nitrostyrene can specific inhibit NLRP3 and reduces PANoptosis in renal ischaemia–reperfusion injury [83].

The ongoing development of inhibitors for PANoptosis holds promise for future therapeutic applications, as the identification of specific inhibitors targeting this process could significantly impact the treatment of a range of diseases, particularly those involving aberrant cell death pathways. Understanding both activators and inhibitors of PANoptosis is crucial for elucidating its roles in various diseases and for developing novel therapeutic strategies.

PANoptosis represents a unique inflammatory programmed cell death pathway characterised by the intricate interplay and activation of various cell death-associated molecules, culminating in the formation of PANoptosome complexes. These complexes play a pivotal role in regulating PANoptosis and are implicated in a diverse array of pathological conditions, including microbial infections, cancers, metabolic dysfunction-related steatotic liver disease, ALF, ischaemia–reperfusion injury, and organ failure. The regulatory nature of PANoptosis arises from the complex interactions of multiple molecular mechanisms within the cell, generating a distinct inflammatory response that is essential for pathogen elimination and the maintenance of tissue homeostasis. Elucidating the molecular basis and the regulatory approach of PANoptosis is critical to advancing therapeutic strategies aimed at modulating cell death in a variety of disease conditions, including liver disease.

5.1 PANoptosis in ALI

ALI is a common disease characterised by a rapid deterioration of liver function due to massive hepatocyte death over a short period, typically within 2 weeks [84]. It poses a serious threat to patient health and can be caused by various aetiologies, including drug-induced hepatotoxicity, ischaemia–reperfusion injury, autoimmunity, and viral hepatitis [85]. PANoptosis plays a significant role in ALI, particularly in the response of hepatocytes to various stressors and insults. In the context of ALI, hepatocytes can undergo PANoptosis due to the activation of specific signalling pathways [73]. PAMPs or DAMPs can trigger the pathways leading to PANoptosis [86].

In a study on ALI induced by excessive acetaminophen (APAP), it was found that APAP overdose triggers multiple forms of programmed cell death in hepatocytes, including pyroptosis, apoptosis, and necroptosis, while also inducing neutrophil activation. Activated neutrophils migrate to the site of injury and participate in hepatocyte damage by forming neutrophil extracellular traps (NETs), contributing to the progression of APAP-induced ALI. In the ALI mouse model induced by APAP, PANoptosis occurs alongside a significant increase in NETs markers (such as myeloperoxidase and citrullinated histone H3) in liver tissue and serum. Preinjection of DNase1 significantly inhibits NETs formation, reduces PANoptosis, and alleviates APAP-induced ALI. Additionally, AIM2 is involved in this process, as knocking down AIM2 eliminates NETs-induced PANoptosis in HepaRG cells. In AIM2 knockout mice, the ALI associated with excessive APAP is significantly reduced, and the occurrence of PANoptosis is also less frequent. This suggests that neutrophils, through NETs, participate in the hepatocyte damage and PANoptosis processes, potentially serving as a new therapeutic target for treating ALI [14]. PANoptosis contributes to the inflammatory response observed in ALI. The release of pro-inflammatory cytokines and danger signals during PANoptosis can activate immune cells, further propagating inflammation within the liver. Activated immune cells, including Kupffer cells and infiltrating lymphocytes, may contribute to a cycle of inflammation and cell death, exacerbating liver injury [87]. Understanding the role of PANoptosis in ALI opens up potential therapeutic avenues. Research into inhibitors of specific molecules involved in the PANoptosis pathway, such as caspases and other cellular effectors, may have therapeutic relevance for conditions like ALF and acute hepatitis.

5.2 PANoptosis in Liver Failure

Liver failure is a common clinical syndrome of severe liver disease. ALI can be transformed into liver failure in severe cases, and liver failure often results in severely impaired or dysfunctional hepatic synthesis, detoxification, metabolism, and biotransformation, with an extremely high mortality rate. Liver failure can be divided into four categories: ALF, subacute liver failure, acute-on-chronic (subacute) liver failure (ACLF), and chronic liver failure. Viruses, drugs, and autoimmune diseases are the main causes of liver failure in normal individuals. In recent years, alcohol abuse and metabolic syndrome have also become significant causes of liver failure [88, 89]. The high mortality rate of ALF creates an enormous health and economic burden worldwide. Currently, there is still a lack of effective treatment options for ALF, and liver transplantation remains the only recommended therapeutic approach. However, the application of liver transplantation is limited due to the scarcity of donor organs and the constraints of organ rejection. Therefore, in-depth research into the pathophysiological mechanisms of ALF may provide new strategies for its clinical treatment [90].

In ALF or ACLF, PANoptosis involves the activation of the immune system and the regulation of inflammatory responses. Acute triggers can activate immune cells and inflammatory cytokine pathways, leading to hepatocyte damage and necrosis. Research indicates that in an LPS/D-Gal-induced cell injury model, decreased cell viability, increased lactate dehydrogenase release, and higher cell death observed by PI staining are accompanied by increased levels of PANoptosis-related molecules in the LPS/D-Gal group compared to controls, indicating elevated PANoptosis levels in ALF. Furthermore, deacetylated MDH1 and IDH1 have been found to exacerbate PANoptosis in ALF through endoplasmic reticulum stress signalling. In ALF, deacetylated MDH1 and IDH1 weaken the inhibitory effect of the histone deacetylase inhibitor ACY1215 on PANoptosis, suggesting that the acetylation status of MDH1 and IDH1 impacts PANoptosis. In a mouse model, the deacetylated forms of MDH1 and IDH1 exacerbated liver tissue damage and increased PANoptosis levels in the liver tissue of ALF mice [36]. It has also been found that intestinal endotoxaemia could inhibit the expression of TAK1 by binding to TLR4 molecules and promote hepatocyte PANoptosis during ALF. In this context, promoting TAK1 expression could effectively relieve LPS-induced hepatocyte PANoptosis. Therefore, if we can effectively promote the expression of TAK1, it may serve as an effective target for the treatment of ALF, alleviating PANoptosis in hepatocytes induced by intestinal endotoxaemia [91].

Research into selectively inhibiting components of the PANoptosis pathway may yield new treatments for ALF. A deeper grasp of its role in liver failure could lead to more effective therapies and better patient outcomes. PANoptosis is critical to the pathophysiology of liver failure through its impact on inflammation and cell death, and exploring these mechanisms may inform new treatment strategies and enhance clinical management.

5.3 PANoptosis in Metabolic Dysfunction-Associated Fatty Liver Disease

MASLD is a group of fatty liver diseases associated with systemic metabolic disorders, the prevalence of MASLD is 33.0% [92, 93]. The pathogenesis of MASLD is complex and mainly includes lipid metabolism abnormalities, inflammatory responses, hepatocellular injury and cell death, genetic and environmental factors, and gut microbiome dysbiosis.

In the context of MASLD, hepatocytes undergo metabolic stress due to excessive lipid accumulation, insulin resistance, and oxidative stress. These factors collectively activate the process known as PANoptosis [13, 94]. The accumulation of surplus lipids within liver cells results in the release of DAMPs, which can initiate inflammatory signalling through pathways, such as the TNF-α axis critical for the onset of PANoptosis [63, 95]. In MASLD, apoptosis, pyroptosis, and necroptosis encompassed by PANoptosis can occur concurrently. Numerous factors trigger apoptosis in MASLD conditions, most of which are linked to mitochondrial dysfunction. Damage to the mitochondria can lead to mitochondrial outer membrane permeabilisation, resulting in the release of Cyt c into the cytoplasm. Once in the cytoplasm, Cyt c binds to Apaf-1 and pro-Caspase-9, facilitating the formation of apoptosomes that activate downstream caspases, ultimately leading to apoptotic cell death [96]. In patients with non-alcoholic steatohepatitis, excessive lipid accumulation promotes the generation of ROS. Elevated ROS levels, combined with excessive calcium ion (Ca²⁺) accumulation, can result in sustained mitochondrial permeability transition pore activation and the release of potent pro-apoptotic factors, such as Cyt c [97, 98]. Additionally, pyroptosis plays a significant role in hepatocyte death associated with MASLD. Here, TNF-α activates downstream signalling pathways via TNF receptor 1, which contributes to the activation and maturation of the NLRP3 inflammasome, culminating in the release of inflammatory cytokines IL-1β and IL-18 [99]. This cascade exacerbates the inflammatory response and leads to the swelling and rupture of hepatocytes. Moreover, necrotic apoptosis a programmed cell death mechanism contributes to pathological hepatocyte death in non-alcoholic steatohepatitis. This form of cell death results in the release of DAMPs, further triggering an inflammatory cascade through the activation of Kupffer cells, ultimately leading to hepatocyte swelling and subsequent cell death [100, 101].

In summary, PANoptosis represents a critical mechanism involved in the progression of MASLD. Further research is essential to fully elucidate the role of PANoptosis in MASLD and its potential as a target for treatment.

5.4 PANoptosis in HCC

Liver cancer was the eighth most common cause of cancer responsible for 485 000 deaths, which accounted for 0.86% of total global deaths [102]. The most common of all liver cancers is primary liver cancer, HCC accounts for 80%–90% of primary liver cancers. There are many causes of primary liver cancer, with the spread of the hepatitis B virus vaccine and the improvement of people's living environment, metabolic alterations have gradually become a major factor in these factors leading to primary liver cancer [103].

PANoptosis's role in cancer is intricate. It can prevent tumorigenesis by clearing damaged cells, maintaining homeostasis, and protecting against malignancy [104]. However, overactivation in the tumour microenvironment may inadvertently promote cancer by killing immune cells that suppress tumours, aiding immune evasion and inflammation-driven oncogenesis [105]. With regard to HCC, PANoptosis is activated by a variety of stimuli, particularly during infection or cellular stress responses. It may play a crucial role in the tumour microenvironment and cancer progression [106, 107]. The molecular mechanisms underlying PANoptosis in HCC involve the activation of multiple cell death pathways, which can be co-activated within the same cell. This complex interplay is mediated by a multiprotein complex known as the PANoptosome, which engages multiple modes of cell death. The PANoptosome complex includes key proteins, such as ZBP1, caspases, NLRP3, RIPK1, and RIPK3, these proteins are involved in significant crosstalk events within PANoptosis, and their dysregulation has been observed in HCC [108-111]. The activation of PANoptosis in HCC can lead to the release of DAMPs, which can trigger an inflammatory response and further contribute to the disease progression. Moreover, the expression levels of many PANoptosis-related genes, such as NLRP3, Caspase-8, and TNFAIP3, are aberrant in HCC, with significant mutations detected [109, 112].

Targeting PANoptosis in HCC is a promising therapeutic approach, as it allows for the selective modulation of key molecules in the PANoptosis pathway, potentially leading to the effective elimination of cancer cells. This process is crucial in HCC progression, and further research is needed to explore its role and therapeutic potential fully.

5.5 PANoptosis in Other Liver Diseases

PANoptosis also occupies an indelible place in other liver injuries and liver diseases, including sodium sulphite (SS) exposure, mechanical ventilation, and arsenic exposure. SS is a common additive in food and pharmaceuticals, but excessive exposure can induce PANoptosis in hepatocytes. Research indicates that SS leads to the accumulation of mitochondrial ROS, activating the BAX/Bcl-2/Caspase-3 pathway, which triggers apoptosis and activates RIPK1/RIPK3/p-MLKL, resulting in cell necrosis. Furthermore, SS may cause the release of cathepsin B due to p-MLKL-mediated lysosomal membrane permeabilisation, activating NLRP3-dependent pyroptosis [12]. Mechanical ventilation can cause extrapulmonary organ damage, including liver injury, by negatively affecting the lungs and increasing inflammatory cytokine secretion. HMGB1 protein acts as a pro-inflammatory mediator in ventilator-associated lung injury and triggers NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway, resulting in liver damage. Inhibiting NETs formation may alleviate liver damage, suggesting that HMGB1 is a potential therapeutic target for liver injury associated with mechanical ventilation [113]. Arsenic exposure leads to environmental pollution known as arsenic contamination and increases the risk of multi-organ toxicity. Studies indicate that arsenic-induced liver toxicity in chickens is linked to PANoptosis. Arsenic treatment elevates ZBP1 protein levels, resulting in abnormal expression of apoptosis-related factors, pyroptosis-related factors, and necrosis-related factors [114].

In conclusion, PANoptosis plays a role in liver diseases by modulating inflammatory responses, promoting cell clearance, and influencing metabolism and tumorigenesis in a variety of ways. To show more clearly the role of PANoptosis in various liver diseases, we summarised in Table 2. An in-depth study of the specific mechanisms of PANoptosis may provide new targets for the treatment of liver diseases and help develop more effective therapeutic strategies to improve the prognosis of patients.