Targeting PANoptosis in Bacterial-Induced Inflammatory Diseases: Mechanisms and Therapeutic Interventions

Tianyin Wang,¹ Yini Lu,¹ Xiong Zhang,² Feng Yu¹

¹Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, People’s Republic of China; ²Department of Criminal Science and Technology, Jiangsu Police Institute, Nanjing, Jiangsu, 210031, People’s Republic of China

Correspondence: Xiong Zhang, Department of Criminal Science and Technology, Jiangsu Police Institute, Nanjing, Jiangsu, 210031, People’s Republic of China, Email [email protected] Feng Yu, Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing, Jiangsu, 211198, People’s Republic of China, Email [email protected]

Abstract: PANoptosis is a novel form of cell death that integrates necroptosis, apoptosis, and pyroptosis, along with their crosstalk, mediated and regulated by the PANoptosome. This review focuses on bacterial PANoptosis, systematically summarizing through distinct pathways and virulence factors, and analyzing its role in inflammatory diseases. Furthermore, we discuss potential therapeutic interventions related to PANoptosis in bacterial inflammation, establishing a framework for novel anti-inflammatory drug development. Understanding the mechanisms of bacteria-induced PANoptosis may provide new strategies for targeted intervention in inflammatory responses to infection.

Keywords: PANoptosis, PANoptosome, gram-positive bacteria, gram-negative bacteria, potential therapeutic targets

Introduction of PANoptosis

PANoptosis

Programmed cell death is a genetically regulated process that maintains cellular homeostasis through distinct death pathways in response to environment-specific stimuli.¹ Beyond conventional death modalities, a novel programmed cell death pathway termed PANoptosis has been recognized. The PANoptosis paradigm first emerged in 2019. Researchers analyzing the functions of Z-DNA binding protein 1 (ZBP1) and transforming growth factor-β-activated kinase 1 (TAK1) molecules demonstrated that apoptosis, pyroptosis, and necroptosis could be integrated into a synergistic PANoptosis pathway, establishing that these three forms of cell death are interconnected rather than independent.² Accumulating data revealed extensive crosstalk between these processes,³ leading to the conceptual maturation of PANoptosis. PANoptosis represents a unique programmed cell death modality that integrates characteristic elements of apoptosis, pyroptosis, and necroptosis while maintaining its own identity distinct from each constituent pathway.

PANoptosome

The PANoptosome serves as the core complex regulating PANoptosis,⁴ incorporating key regulatory proteins from all three death pathways to initiate downstream necroptosis, apoptosis, and pyroptosis. Currently, four distinct types of PANoptosomes have been identified: ZBP1-, absent in melanoma 2 (AIM2)-, receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, and NLR family pyrin domain containing 12 (NLRP12)-PANoptosomes, each possessing unique components and activation mechanisms.⁵ (1) The ZBP1-PANoptosome assembles upon ZBP1 activation through its Zα2 domain recognition of viral Z-RNA. This triggers receptor-interacting protein (RIP) homotypic interaction motif (RHIM) domain mediated homotypic interaction with RIPK3, forming the core complex.^6,7 Caspase-6 reinforces this assembly by directly binding RIPK3 and enhancing RHIM-dependent ZBP1-RIPK3 engagement.⁸ This stabilized core complex subsequently recruits Caspase-8 and activates the NLRP3 inflammasome, thereby amplifying inflammatory signaling and triggering PANoptosis. (2) The AIM2-PANoptosome assembles when AIM2 binds pathogenic or host-derived double-stranded DNA. Through its pyrin domain, AIM2 recruits the apoptosis-associated speck-like protein containing a CARD (ASC) adaptor to form the inflammasome core and activate Caspase-1.^9,10 Under specific conditions, AIM2 cooperates with pyrin and ZBP1 to form the AIM2-PANoptosome complex.^11,12 This complex integrates ASC, Caspase-1, Caspase-8, RIPK3, RIPK1 and Fas-associated protein with death domain (FADD), collectively activating PANoptosis. (3) The RIPK1-PANoptosome is activated during Yersinia infection or TAK1 inhibition. Its assembly depends on the protein phosphatase 6 (PP6) phosphatase complex, with RIPK1 and RIPK3 serving as the central protein in PANoptosis regulation.^13,14 The N-terminal kinase domain of RIPK1 is critical for inducing cell death.¹⁵ RIPK3 serves as an essential component of the necrosome, interacts with RIPK1 to trigger programmed necrosis, and plays a pivotal role in PANoptosis regulation.¹⁶ (4) The NLRP12-PANoptosome responds to signals including heme, tumor necrosis factor (TNF), and pathogen-associated molecular patterns (PAMPs),¹⁷ driving PANoptosis in hemolysis and inflammatory diseases through caspase-8 and RIPK3.^18,19

Shared Mechanisms of PANoptosis in Gram-Positive and Gram-Negative Bacteria

Both Gram-positive and Gram-negative bacteria can trigger PANoptosis through distinct molecular mechanisms. Virulence factors from both bacterial types activate host cell death signaling pathways through different molecular mechanisms, ultimately converging on PANoptosome complex formation. This molecular scaffold integrates key components from the inflammasome (ASC, NLRP3, caspase-1), apoptosome (caspase-8), and necrosome (RIPK3), simultaneously activating caspase-3-mediated apoptosis, gasdermin D (GSDMD)-mediated pyroptosis, and mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis (Figure 1).

Figure 1 Mechanisms of PANoptosis Induction by Gram-negative and Gram-positive Bacteria.

Bacterial Secretion Systems

The delivery of effectors mediated by bacterial secretion systems constitutes a crucial mechanism for triggering host cell PANoptosis. Predominantly found in Gram-negative bacteria, these secretion systems function to precisely inject effectors into host cells, thereby modulating host signaling pathways to facilitate bacterial invasion, survival, and immune evasion. Gram-negative bacteria employ diverse secretion systems including Type II secretion system (T2SS), T3SS, and T6SS. Notably, Pseudomonas aeruginosa utilizes the T2SS protease LasB to disrupt intercellular junctions²⁰ while simultaneously injecting effectors via T3SS to damage mucosal barriers;²¹ its T6SS effector VgrG2b targets microtubule structures, with these three systems acting synergistically to enhance bacterial infection.^22,23 Similarly, Escherichia coli employs T3SS to inject effectors into the host cytoplasm, inducing impairment of intestinal epithelial tight junctions.²⁴

Toll-Like Receptors (TLRs)

TLRs, a family of pattern recognition receptors (PRRs) in the innate immune system, mediate early pathogen detection.²⁵ While playing pivotal roles in antibacterial immune responses, TLRs exhibit distinct recognition mechanisms and immunoregulatory functions toward Gram-negative versus Gram-positive bacteria. For Gram-negative bacteria, TLR4 serves as the primary receptor that initiates myeloid differentiation primary response 88 (MyD88)-dependent signaling upon lipopolysaccharide (LPS) binding, eliciting robust inflammatory responses, which may progress to cytokine storms when hyperactivated.²⁶ In contrast, Gram-positive bacteria are predominantly recognized by TLR2 through specific components such as lipoproteins and peptidoglycan. For instance, TLR2-mediated detection of Staphylococcus aureus enhances neutrophil phagocytic activity to combat infection,²⁷ whereas excessive TLR2 recognition of Clostridioides difficile toxins may exacerbate tissue damage.²⁸

PAMPs

PRRs detect PAMPs or damage-associated molecular patterns (DAMPs), triggering signaling cascades that initiate PANoptosis.^2,4 In Gram-positive bacteria, the predominant PAMPs are peptidoglycan (PGN) and lipoteichoic acid (LTA), which are exposed on the bacterial surface^29–31 and activate inflammatory pathways through TLR2 or nucleotide-binding oligomerization domain (NOD)-like receptors. The secreted exotoxins from these bacteria serve as major effector molecules that can activate inflammasomes and trigger PANoptosis. The primary PAMP of Gram-negative bacteria is LPS, which is expressed on the bacterial surface. LPS activates inflammasomes through TLR4,^29,30,32 inducing robust inflammatory responses that subsequently promote PANoptosis.

Exemplars of PANoptosis in Bacteria

Gram-Positive Cocci

Staphylococcus aureus (S. aureus)

S. aureus dynamically modulates host cell PANoptosis through multiple virulence factors. Regarding apoptosis, S. aureus secreted alpha-toxin (α-toxin) and staphylococcal enterotoxins (SEs) directly trigger apoptosis.³³ Its extracellular vesicles (EVs) invade cells via lipid raft-mediated endocytosis, inducing mitochondrial damage and activating mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways to promote apoptosis.³⁴ Conversely, this pathogen can also suppress apoptosis by inhibiting caspase-8 to facilitate immune evasion,³⁵ or disrupt the crosstalk between neutrophil autophagy and apoptosis to sustain infection.³⁶ In pyroptotic regulation, the pore-forming toxin Panton-Valentine leukocidin (PVL) binds the LukS-PV subunit on monocytes and macrophages to activate the NLRP3 inflammasome, driving caspase-1-dependent interleukin-1 beta (IL-1β) and IL-18 release.³⁷ While LTA activates caspase-11 and caspase-1 via NLRP6 to regulate IL-18 secretion, demonstrating inflammasome synergy.³⁸ Regarding necroptosis, toxin-mediated activation of RIPK1/RIPK3/MLKL signaling is the key mechanism,³⁹ and AIM2 inflammasome-mediated macrophage necroptosis enhances bacterial pathogenicity.⁴⁰ This multi-pathway cell death modulation reveals S. aureus infection strategies: either promoting PANoptosis to facilitate toxin dissemination or suppressing PANoptosis to evade host clearance.

Streptococcus pneumoniae (S. pneumoniae)

S. pneumoniae modulates host cell PANoptosis through multiple pore-forming toxins. In apoptotic regulation, S. pneumoniae cholesterol-dependent cytolysins induce apoptosis in neurons and epithelial cells.⁴¹ In chronic obstructive pulmonary disease (COPD) patients, S. pneumoniae triggers macrophage apoptosis and reactive oxygen species (ROS) release;⁴² whereas alveolar macrophage caspase-dependent apoptosis associated with ROS and nitric oxide (NO) production is crucial for bacterial clearance.⁴³ This differential regulation demonstrates that S. pneumoniae-induced apoptosis disrupts tissue barriers, while macrophage apoptosis facilitates bacterial clearance and inflammation control. Pyroptosis is primarily activated by pneumolysin (PLY) through NIMA-related kinase 7 (NEK7)–NLRP3 inflammasome assembly, leading to caspase-dependent IL-1β maturation.⁴⁴ Different inflammasomes exhibit synergistic defense: NLRP6-deficient mice show reduced pyroptosis and higher survival rates than wild-type mice during S. pneumoniae infection,⁴⁵ while AIM2-deficiency impairs caspase-1 activation and IL-1β secretion, increasing infection susceptibility.⁴⁶ Regarding necroptosis, hemolysins and other pore-forming toxins activate both the typical RIPK1/RIPK3/MLKL pathway⁴⁷ and direct ion dysregulation.⁴⁸ RIPK3 forms complexes with RIPK1, MLKL, and mitochondrial calcium uniporter (MCU) to stimulate Ca²⁺ uptake into mitochondria and subsequent mitochondrial ROS (mROS) production in S. pneumoniae infection, promoting bacterial clearance.⁴⁹ However, aberrant necroptosis with low NF-κB activation exacerbates lung injury.⁵⁰ This dual role makes PANoptosis both a defensive weapon and potential contributor to infection pathology.

Gram-Positive Bacilli

Bacillus anthracis (B. anthracis)

B. anthracis exerts its pathogenic effects primarily through lethal toxin (LeTx)-mediated modulation of PANoptosis during infection. LeTx activates the NLRP3 inflammasome via TNF signaling, with caspase-8/RIPK3-deficient mice demonstrating enhanced resistance to infection, confirming this pathway’s significance.⁵¹ Simultaneously, LeTx specifically activates NLRP1b and NLR family CARD domain containing 4 (NLRC4) inflammasomes, exhibiting dual functionality: it recruits FADD through ASC to trigger caspase-8-dependent apoptosis⁵² while also inducing caspase-1-dependent pyroptosis and IL-1β release through potassium efflux.^53,54 Regarding necroptosis, LeTx enhances TNF-α-induced intestinal epithelial cell death by suppressing p38α MAPK, concurrently activating both caspase-dependent apoptosis and RIPK3/MLKL-mediated necroptosis.⁵⁵ These findings reveal that B. anthracis orchestrates cell death through multifaceted regulation involving toxins and inflammasomes, simultaneously promoting pathogen dissemination and exacerbating tissue damage.

Listeria monocytogenes (L. monocytogenes)

L. monocytogenes primarily induces host cell death through its key virulence factor listeriolysin O (LLO). In lymphocytes, LLO directly triggers dose-dependent apoptosis and enhances host susceptibility.⁵⁶ In glial cells, L. monocytogenes induces apoptosis, while inhibition of bacterial ROS further promotes apoptotic cell death.⁵⁷ Regarding pyroptosis, in macrophages, L. monocytogenes promotes the interaction between Nek7 and NLRP3 through the c-Jun N-terminal kinase (JNK) signaling pathway, driving caspase-1-dependent pyroptosis.⁵⁸ Bacterial DNA released during lysis triggers AIM2 inflammasome-dependent pyroptosis.⁵⁹ Depletion of Mint3 promotes pyroptosis in host macrophages and prevents L. monocytogenes infection spread, indicating that Mint3 deficiency enhances host defense.⁶⁰ Furthermore, in necroptosis regulation, the RIPK3-MLKL pathway exhibits dual modulation: it can clear infection through classical necroptosis while directly inhibiting intracellular bacterial replication in a cell death-independent manner.^61,62

Other Gram-Positive Bacteria

Gram-positive bacteria with specialized morphologies play crucial roles in host–pathogen interactions by modulating programmed cell death. Actinomyces species activate the NLRP3 inflammasome through TLR2-dependent mechanisms, inducing macrophage pyroptosis characterized by GSDMD cleavage and IL-1β/IL-18 release.⁶³ Nocardia produces heme-binding protein (HBP) that targets mitochondria to trigger caspase-3-dependent apoptosis.⁶⁴ These bacteria display biphasic apoptotic control during macrophage infection: first activating extrinsic and intrinsic pathways with increased caspase-8/9 expression, then suppressing apoptosis.⁶⁵ Streptomyces-derived secondary metabolites can simultaneously induce tumor cell apoptosis and necroptosis.⁶⁶

Gram-Negative Cocci

Neisseria

Neisseria gonorrhoeae exhibits cell type-specific regulation of apoptosis, delivering outer membrane protein PorB to mitochondria via outer membrane vesicles (OMVs) to induce THP-1 macrophage apoptosis⁶⁷ while suppressing apoptosis in U937 cells and primary human macrophages.⁶⁸ In polymorphonuclear leukocytes (PMNs), it inhibits caspase-3/7/9 to prolong PMN survival and promote bacterial dissemination.^69,70 For pyroptosis, this pathogen activates both canonical (caspase-1) and non-canonical (caspase-4) pathways through TLR2-NLRP3 signaling, triggering GSDMD-dependent pyroptosis with IL-1β/IL-18 release; NLRP3 deficiency enhances macrophage bactericidal activity, suggesting that pyroptosis may compromise host defense.^71,72 Neisseria meningitidis shows serotype-dependent apoptotic regulation: serogroup W induces stronger apoptosis in human epithelial cells and murine immune cells than serogroup Y, correlating with higher bacteremia levels.⁷³ PorB selectively inhibits intrinsic apoptosis to maintain intracellular survival.⁷⁴ Pyroptosis depends on the HrpA/HrpB two-partner secretion system (TPS) activating caspase-1/11 to cleave GSDMD, accelerating cerebral dissemination via IL-1β/IL-18 release.⁷⁵ HrpA interaction with neuronal dynein light-chain, Tctex-type 1 balances apoptosis and pyroptosis,⁷⁶ while lipooligosaccharide (LOS) coordinates inflammation through TLR4-mediated NF-κB activation and inflammasome assembly.⁷⁷

Moraxella catarrhalis (M. catarrhalis)

M. catarrhalis activates caspase-4/11-GSDMD-dependent pyroptosis through its LOS and OMVs, a process requiring type I interferon (IFN-I) signaling and guanylate-binding proteins (GBPs) with involvement of NLRP3 inflammasome activation.⁷⁸ In lung epithelial cells, M. catarrhalis triggers the mitochondrial apoptotic pathway, characterized by caspase-3/6/9 activation, decreased B-cell lymphoma 2 (Bcl-2) expression, and Bcl-2-associated X protein (Bax) translocation.⁷⁹ Notably, while this bacterium activates B-cell proliferation and surface marker expression, it does not induce B-cell apoptosis.⁸⁰ Furthermore, in severe asthma patients, M. catarrhalis infection correlates with neutrophil extracellular trap pathway (NETosis) formation alongside activation of MAPK, NF-κB, and necroptosis signaling pathways.⁸¹

Gram-Negative Bacilli

Escherichia coli (E. coli)

E. coli regulates host cell PANoptosis through strain-specific mechanisms. Multidrug-resistant strains simultaneously activate apoptotic caspases-3/7/8, pyroptotic caspase-1/GSDMD, and necroptotic RIPK3/MLKL pathways, with amygdalin and chlorogenic acid mitigating this process by inhibiting PANoptosis core proteins.^82,83 In apoptosis, enteroaggregative E. coli induces intestinal epithelial cell apoptosis through both Bax/Bak upregulation and caspase-8 activation,⁸⁴ causing DNA fragmentation and cell cycle arrest.⁸⁵ Enterotoxigenic E. coli (ETEC) demonstrates selective regulation in piglet models by suppressing caspase-9 while activating caspase-8.⁸⁶ For pyroptosis, ETEC K88 and mastitis-associated strains trigger canonical pyroptosis via NLRP3/caspase-1 axis,^87–89 exacerbating inflammation. Whereas, enteropathogenic E. coli (EPEC) activates non-canonical pyroptosis through T3SS-dependent caspase-4 activation.⁹⁰ GSDMB binding to caspase-4 promotes non-canonical pyroptosis, while caspase-7 creates negative feedback through GSDMB cleavage.⁹¹ Regarding necroptosis, extraintestinal pathogenic E. coli enhances RIPK1/MLKL signaling via outer membrane protein TolC,⁹² reversible by RIPK1 inhibitor necrostatin-1 (Nec-1).⁹³ Whereas EPEC degrades RIPK1, RIPK3, TIR-domain-containing adapter-inducing interferon-β, and ZBP1 through T3SS to actively suppress necroptosis for immune evasion.⁹⁴

Salmonella spp.

Salmonella Typhimurium induces apoptosis, pyroptosis, and necroptosis in host cells. This pathogen triggers both apoptosis and necroptosis during Caco-2 cell invasion while promoting the release of proinflammatory cytokines IL-8 and TNF-α.⁹⁵ Additionally, Salmonella drives pyroptosis through inflammasome pathway activation, which worsens gut inflammation. A novel heteropolysaccharide (EPS 7–4) inhibits Salmonella Typhimurium-induced pyroptosis by blocking ASC oligomerization, helping to reduce intestinal damage.⁹⁶ These findings reveal how Salmonella differentially regulates cell death pathways to promote infection, offering new perspectives for targeted therapies.

Yersinia spp.

Yersinia modulates host cell death programs through multifaceted mechanisms. In PANoptosis regulation, these pathogens trigger RIPK1-dependent PANoptosome assembly, coordinately activating caspase-1, caspase-8, and MLKL pathways.¹³ RIPK1 plays a central regulatory role, where its deficiency suppresses pyroptosis and apoptosis while enhancing necroptosis.¹³ The Yersinia effector protein YopJ induces caspase-8-dependent GSDMD cleavage, driving non-canonical pyroptosis,⁹⁷ with RIPK1 autophosphorylation at T169 being critical for this process.⁹⁸ Metabolically, Yersinia pseudotuberculosis activates AMP-activated protein kinase (AMPK) through glucose depletion, promoting RIPK1 phosphorylation at S321 to inhibit pyroptosis.⁹⁹ Lysosomal supercomplexes precisely regulate pyroptosis intensity by recruiting RIPK1-caspase-8 assemblies.¹⁰⁰ This cell death regulation exhibits species specificity. Yersinia-infected murine macrophages undergo extrinsic apoptosis via the RIPK1-caspase-8 axis, while human macrophages trigger RIPK1-independent apoptosis through inhibitor of kappa B kinase (IKK) inhibition.¹⁰¹

Pseudomonas aeruginosa (P. aeruginosa)

In P. aeruginosa-induced PANoptosis, macrophage cell death can only be completely blocked when caspase-1, −11, −8 and RIPK3 are simultaneously absent.¹⁰² The RIPK1/MLKL pathway shows compensatory enhancement when neuronal apoptosis inhibitory protein 5 and NLRC4 are deficient.¹⁰² Regarding apoptosis, the T3SS effector ExoT activates JNK1/2 signaling through its GTPase-activating protein (GAP) domain, inducing caspase-9/caspase-3-mediated apoptosis,¹⁰³ while exotoxin A markedly increases caspase-3 activity to promote hemocyte apoptosis.¹⁰⁴ In pyroptosis regulation, flagellin activates the NLRC4 inflammasome, triggering caspase-1/GSDMD-dependent pyroptosis in macrophages and neutrophils.^105,106 In keratitis models, caspase-4/5/11-mediated non-canonical pyroptosis causes corneal cell death.¹⁰⁷ For necroptosis, P. aeruginosa employs quorum sensing-mediated precise control, where rhl subsystem deficiency enhances RIPK3/MLKL-dependent necroptosis.¹⁰⁸ During respiratory infection, CYP450 activation triggers club cell necroptosis which disrupts epithelial barriers, with Nec-1 showing reversal effects.¹⁰⁹ These mechanisms collectively represent P. aeruginosa’s multifaceted strategies to breach host defenses.

Other Gram-Negative Bacteria

Vibrio species, as a major group of Gram-negative bacteria, modulate host PANoptosis through diverse virulence mechanisms. Vibrio alginolyticus triggers caspase-8/-9/-3-dependent apoptosis and cytolysis in fish cells via T3SS.¹¹⁰ Vibrio proteolyticus hemolysin VPRH activates caspase-1 by NLRP3 inflammasome, inducing IL-1β release and pyroptosis.¹¹¹ Vibrio fluvialis hemolysin activates the NLRP3-caspase-1-GSDMD axis via K⁺ efflux and Ca²⁺ influx.¹¹² For necroptosis, Vibrio vulnificus cytolysin upregulates pMLKL to drive necroptosis, which resveratrol can ameliorate in sepsis models.¹¹³

PANoptosis in Bacterial Inflammatory Diseases

Sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹¹⁴ This condition represents a major global health challenge, with annual estimates of 31.5 million cases and 5 million deaths worldwide,¹¹⁵ prompting the World Health Organization to designate sepsis as a global health priority.¹¹⁶

Analysis of PANoptosis-related genes (PRGs) and associated immune signatures in sepsis datasets reveals dysregulated PRG expression in patients, highlighting the complex interplay between sepsis and PANoptosis.¹¹⁷ Our previous studies also revealed that severe apoptosis occurs in the liver, kidney, and other tissues during the progression of sepsis.¹¹⁸ Proinflammatory cytokines play pivotal roles in sepsis-associated PANoptosis. Combined TNF-α and IFN-γ treatment induces PANoptosis, while neutralizing antibodies against these cytokines suppresses PANoptosis progression and improves survival in septic mice.¹¹⁹

Addressing sepsis-induced organ dysfunction remains a critical challenge, with distinct PANoptosis activation patterns across organs. In cardiac tissue, Xiao Chai Hu Tang exerts protective effects by suppressing ZBP1-mediated PANoptosis, whereas ZBP1 overexpression exacerbates cardiomyocyte death.¹²⁰ During renal injury, AIM2 expression is significantly upregulated and promotes PANoptosis in renal tubular epithelial cells through eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) regulation.¹²¹ In the lungs, which represent the most frequently affected organ in sepsis, the ZBP1 and RIPK1 play a key role in pulmonary epithelial PANoptosis.¹²² Lactic acidosis aggravates ZBP1-dependent PANoptosis in pulmonary vascular endothelial cells during acute lung injury.¹²³ Collectively, these findings demonstrate marked organ-specificity in PANoptosis activation during sepsis: ZBP1 predominantly mediates cardiac and pulmonary injury, while AIM2 plays a more prominent role in renal damage. This organ-specific pattern provides a theoretical basis for developing targeted organ-protective strategies.

Lung Diseases

Community-acquired pneumonia (CAP) represents the most common infectious cause of adult hospitalizations and deaths in the United States. A substantial proportion of CAP cases progress to sepsis and acute respiratory distress syndrome (ARDS).¹²⁴ Pneumonia serves as the primary infectious trigger for ARDS.¹²⁵ As a frequent cause of respiratory failure in critically ill patients, ARDS meets diagnostic criteria in approximately 10% of global intensive care unit admissions, with mortality rates reaching 30–40%.¹²⁶

Abnormal PANoptosis activation is closely associated with bacterial pneumonia progression, involving coordinated regulation of multiple signaling pathways. Transcriptomic analysis reveals significantly altered expression of PANoptosis signature genes including zinc finger protein 304 (ZNF304), AKT serine/threonine kinase 3 (AKT3), MAPK8, and Rho GTPase activating protein 10 (ARHGAP10) in CAP patients, indicating their biomarker and therapeutic potential.¹²⁷ During pathogen infection, IFN-γ is a key PANoptosis regulator. In Pasteurella multocida toxin (PMT)-induced pneumonia models, IFN-γ deficiency significantly reduces expression of executioner proteins including caspase-3, GSDMD and MLKL, while decreasing lung myeloperoxidase activity and IL-1β release, thereby alleviating lung injury.¹²⁸

In pulmonary diseases, PANoptosis activation involves coordinated regulation through multiple pathways. The stimulator of interferon genes (STING) agonist activates NF-κB to promote IFN-I and pro-inflammatory cytokine production, inducing ZBP1-dependent PANoptosis.¹²⁹ Overactivation of the cyclic GMP-AMP synthase (cGAS)-STING pathway promotes PANoptosome assembly, whereas the kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE) significantly attenuates lung injury by inhibiting this pathway.¹³⁰ MiR-29a-3p targets ZBP1 expression, substantially reducing levels of key PANoptosis execution proteins including Caspase-3, Caspase-8, GSDMD, and MLKL in alveolar epithelial cells.¹³¹ Baicalin effectively suppresses PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly.¹³² Collectively, these studies demonstrate that PANoptosis in lung tissue is regulated by multiple signaling nodes including STING, cGAS, and ZBP1, suggesting that targeting these key nodes may represent a promising therapeutic strategy for bacterial pneumonia.

Gastrointestinal Diseases

The global epidemiological evolution of inflammatory bowel disease (IBD) shows developing countries in the emerging stage, while newly industrialized nations are experiencing accelerating incidence.¹³³ Concurrently, Clostridium difficile infection (CDI), an important bacterial gastrointestinal disease, remains primarily hospital-associated but shows significantly increasing community-associated cases affecting younger, healthier populations.¹³⁴

Bacterial infections contribute to gastrointestinal disease pathogenesis by modulating PANoptosis in intestinal epithelial cells (IECs). Studies reveal significant PANoptosis activation in ulcerative colitis (UC) patients’ IECs, characterized by upregulated key genes including ZBP1, AIM2, caspase-1/8, and interferon regulatory factor 1 (IRF1), where IRF1 potentially acts as a transcription factor promoting PANoptosome complex formation and subsequent intestinal barrier disruption.¹³⁵ In IBD, PANoptosis signature genes strongly correlate with TNF, NF-κB signaling, and immune cell infiltration.¹³⁶ IBD-associated mitochondrial dysfunction and mtROS accumulation exacerbate this process, while selenium-modified exosomes can suppress PANoptosis by scavenging mtROS.¹³⁷ Mechanistically, the Salmonella effector protein SopF inhibits caspase-8 via phosphoinositide-dependent protein kinase-1 (PDK1)-p90 ribosomal S6 kinase signaling, blocking apoptosis and pyroptosis while promoting necroptosis to facilitate bacterial immune evasion.¹³⁸ Colitis mice exhibit elevated expression of PANoptosis-related genes including ZBP1 and caspase-1, which the natural compound diosmin can reverse while maintaining epithelial barrier function and modulating gut microbiota, demonstrating therapeutic potential for colitis.¹³⁹ These findings illustrate how bacteria activate PANoptosis either directly by hijacking cell death programs or indirectly through dysbiosis, ultimately compromising intestinal barrier integrity, with targeting PANoptosis key components representing a promising strategy against bacterial gastrointestinal infections.

Potential Therapeutic Targets and Drugs for PANoptosis in Bacterial Inflammatory Diseases

Bacterial infection-induced inflammatory diseases can activate PANoptosis through multiple mechanisms, with their molecular targets and intervention strategies emerging as research priorities. At the target level, PRR pathways, cell death regulatory nodes, and immune modulators constitute core components of PANoptosis regulation. Potential therapeutic agents can be categorized into three classes: chemical drugs, natural extracts, and traditional Chinese medicine formulations, which differentially modulate inflammatory factors and cell death execution proteins to provide novel therapeutic possibilities for conditions like sepsis and acute lung injury. The following tables systematically summarize the mechanisms of relevant targets and potential drugs (Tables 1 and 2).

Table 1 Potential Therapeutic Targets for PANoptosis in Bacterial Inflammatory Diseases

Table 2 Potential Therapeutic Drugs for PANoptosis in Bacterial Inflammatory Diseases

Discussion

PANoptosis, as an inflammatory programmed cell death pathway that integrates pyroptosis, apoptosis, and necroptosis, forms a sophisticated PANoptosome complex. ZBP1-PANoptosome activates by binding RIPK3 through its Zα2 domain. AIM2-PANoptosome detects double-stranded DNA and integrates pyrin with ZBP1. RIPK1-PANoptosome activates during Yersinia infection or TAK1 inhibition. NLRP12-PANoptosome responds to heme and TNF signals. These complexes possess distinct characteristic components while sharing common elements including caspase-8, RIPK3, and ASC, creating molecular crosstalk that synchronizes multiple cell death programs. Bacterial pathogens engage this network through their characteristic signatures. Gram-positive bacteria primarily activate TLR2/NOD pathways, while Gram-negative bacteria activate LPS-TLR4 signaling. Despite their different starting points, all these pathways eventually lead to activation of the core PANoptosis process.

Currently, the primary challenge in PANoptosis-targeted therapy lies in the lack of specific inhibitors. Existing drugs mainly exhibit two limitations: (1) Uncontrollability of single-target agents. Certain inhibitors like necroptosis inhibitor Nec-1 only act on a single node of one cell death pathway. The crosstalk among cell death pathways enables mutual regulation through negative feedback mechanisms. Disruption of this dynamic balance may trigger abnormal activation or suppression of compensatory pathways, thereby increasing therapeutic unpredictability and potential risks. (2) Nonspecificity of multi-target drugs. Some natural extracts or traditional Chinese medicine components exhibit broad-spectrum regulatory effects. For example, our previous studies demonstrated that human urinary kallidinogenase (HUK), a natural substance extracted from human urine, can inhibit PANoptosis-related apoptosis and necroptosis, thereby protecting damaged human umbilical vein endothelial cells (HUVECs). It also exerts protective effects by modulating cell migration and oxidative stress.¹⁵³ Their polypharmacology may cause systemic effects, making it difficult to precisely distinguish direct actions on PANoptosis, while failing to achieve personalized intervention for different bacterial infectious diseases. This highlights the urgent need to develop highly selective PANoptosis modulators through computational modeling and biological approaches to identify specific binding domains that balance efficacy and safety.

As an integral part of host defense mechanisms, complete inhibition of PANoptosis may impair immune clearance functions, potentially increasing risks of persistent bacterial infection or dissemination. Therefore, avoiding complete PANoptosis suppression while preventing infection risks remains a critical challenge. Future studies could explore targeted modulation strategies rather than complete blockade, such as locally selective PANoptosis inhibition at inflammatory foci to improve overall infection outcomes. Additionally, combined antibiotic therapy may achieve sequential bactericidal and anti-inflammatory effects. Antibiotics first eliminate pathogens to reduce infection burden, followed by precise PANoptosis modulator intervention on overactivated cell death pathways, thereby controlling inflammatory damage while preserving host defense functions.

By systematically elucidating the mechanisms through which Gram-negative and Gram-positive bacteria activate PANoptosis via distinct pathways, and summarizing PANoptosis occurrence in bacterial inflammatory diseases along with therapeutic drugs and targets, this review aims to create more possibilities for precision medicine targeting PANoptosis.

Data Sharing Statement

No new data were generated for this review. All discussed information is based on previously published studies cited in the references.

Acknowledgments

Figure 1 was created with Figdraw (www.figdraw.com).

Author Contributions

Wang T: Conceptualization, Writing – original draft, Writing – review & editing. Lu Y: Conceptualization, Formal analysis, Writing – review & editing. Zhang X and Yu F: Conceptualization, Supervision, Writing – review & editing. All authors took part in drafting, revising or critically reviewing the article, gave final approval of the version to be published and agreed on the journal for submission, accepted full accountability for the content.

Funding

This work was supported by The Hospital Pharmaceutical Research Fundation of Nanjing Pharmaceutical Association – Changzhou Siyao (grant number: 2024YX011).

Disclosure

The authors declare no known competing financial or personal interests that could influence this work.

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