Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and PD-L1-mediated immune evasion is a major mechanism of tumor immune suppression and an important target of immune checkpoint blockade. Here, we identified RNF166 as an E3 ubiquitin ligase that promotes immune evasion in HCC. RNF166 expression was upregulated in HCC tissues and correlated with PD-L1 levels, whereas RNF166 did not directly affect the proliferation or apoptosis of HCC cells. In immunocompetent mouse models, RNF166 overexpression accelerated tumor growth and suppressed CD8 + T-cell infiltration and cytotoxic function, while these effects were dependent on PD-L1 signaling and were attenuated in immunodeficient settings. Mechanistically, RNF166 physically interacted with c-Jun and promoted K63-linked ubiquitination of c-Jun at K50/K56, which was associated with reduced K48-linked ubiquitination and enhanced c-Jun stability. Stabilized c-Jun bound to the PD-L1 promoter and promoted PD-L1 transcription, thereby linking RNF166-mediated c-Jun stabilization to tumor immune suppression. Upstream, lactate accumulation increased H3K18la enrichment at the RNF166 promoter and contributed to RNF166 transcriptional upregulation. Therapeutically, pharmacological inhibition of c-Jun with T-5224 enhanced the antitumor effect of anti-PD-L1 blockade. Collectively, our findings delineate a lactate-H3K18la-RNF166-c-Jun-PD-L1 axis that promotes immune evasion in HCC and suggest that targeting RNF166 or the RNF166-c-Jun axis may improve PD-1/PD-L1-based immunotherapy.
Apoptosis has traditionally been viewed as an irreversible, tumor-suppressive process, with mitochondrial outer membrane permeabilization (MOMP) representing the decisive “point of no return” that irrevocably commits cells to death. Classical models described MOMP as a rapid, synchronous, all-or-none event leading to caspase activation and cellular demise. However, accumulating evidence now challenges this binary view, revealing that both MOMP and downstream caspase activity are threshold-dependent processes that can produce diverse non-lethal outcomes. Under specific conditions, cells can survive or recover from MOMP and downstream apoptotic signaling, fundamentally reshaping our understanding of cell fate decisions. Failed apoptosis and anastasis lie at the center of this paradigm shift, revealing unexpected plasticity in apoptotic outcomes. Failed apoptosis occurs when limited MOMP triggers sublethal yet sustained caspase activity, leading to DNA damage, chromosomal instability, and prolonged cellular reprogramming, thereby accelerating oncogenesis and tumor progression. In contrast, anastasis describes a remarkable recovery process in which cells rebound from late-stage apoptosis after the removal of apoptotic stimuli. Recovered cells exhibit acquired enhanced stress tolerance and oncogenic traits, raising concern about their role in therapy failure, cancer progression, and relapse. This review discusses the molecular mechanisms governing MOMP initiation and subsequent apoptotic signaling, with particular emphasis on new insights into the reversibility of apoptosis. It highlights the concepts of failed apoptosis and anastasis as adaptive responses that influence cell fate, integrating current research, experimental tools and challenges, and their physiological relevance and clinical implications. By describing these survival pathways, the review aims to enhance our understanding of the reversibility of apoptosis and emphasize its relevance to cancer progression, metastasis, and resistance to therapy. These insights may help develop more effective cancer treatments and improve patient outcomes.
Copper is an essential trace element required for mitochondrial respiration, redox regulation, iron metabolism, and cellular signalling, but excessive or mislocalised copper can be cytotoxic. Cuproptosis is a recently identified form of regulated cell death in which copper binds to lipoylated mitochondrial proteins, promotes their aggregation, destabilises iron–sulfur cluster proteins, and induces mitochondrial proteotoxic stress. Copper therefore has context-dependent roles in cancer. Physiological copper supports tumour metabolism, angiogenesis, extracellular-matrix remodelling, and selected oncogenic signalling pathways, whereas therapeutic copper depletion can inhibit copper-dependent tumour processes. Conversely, copper ionophores and related approaches may increase intracellular copper sufficiently to induce cuproptosis in metabolically susceptible cancer cells. This review describes systemic and intracellular copper homeostasis, including intestinal absorption, intracellular trafficking, mitochondrial copper distribution, storage, and export. Particular attention is given to CTR1/SLC31A1, the functionally distinct copper-transporting ATPases ATP7A and ATP7B, metallothioneins, copper chaperones, and cytochrome c oxidase assembly factors. We also examine how cancer cells reprogramme copper handling to support proliferation, angiogenesis, metastasis, and immune evasion. Finally, we discuss the molecular basis of cuproptosis, including the roles of FDX1, FDXR, LIAS, DLAT, mitochondrial respiration, protein lipoylation, and iron–sulfur cluster destabilisation. Current evidence indicates that cuproptosis susceptibility varies among tumour types and depends on copper handling, mitochondrial metabolic state, and the integrity of the protein-lipoylation machinery. Defining these determinants will be necessary for the development of tumour-selective copper-targeted therapies.
Oxidative stress plays a significant regulatory role in tumor immune responses and can influence the efficacy of immunotherapy. Accordingly, therapeutic interventions targeting oxidative stress-related mechanisms, whether alone or in combination with other modalities, represent a compelling strategy to enhance cancer therapy. In this study, we first profiled the landscape of oxidative stress responses within the tumor microenvironment by integrating pan-cancer single-cell RNA sequencing datasets, which revealed that cancer-associated fibroblasts (CAFs) possessed the highest oxidative stress response score. Based on this finding, we developed a fibroblast-derived oxidative stress-related signature (FOSR.Sig) by screening for genes most correlated with oxidative stress responses in CAFs. Furthermore, with a machine learning framework, our model achieved exceptional accuracy in predicting ICI response, and its robustness was subsequently validated. Importantly, a prognostic model incorporating the FOSR.Sig was developed using TCGA pan-cancer datasets and LASSO regression analysis, which provides novel prognostic biomarkers applicable across diverse cancer types. Mechanistic investigation of TFG, the top risk score gene, revealed its critical role in the tumor microenvironment through comprehensive in vitro and in vivo experiments and RNA-seq assays. Our study highlights the therapeutic potential of targeting oxidative stress in cancer-associated fibroblasts as a novel strategy to empower antitumor immunity and prevent immune escape. And provide a promising powerful tool for predicting responses to tumor immunotherapy and patient outcomes.
Herpes simplex virus type 1 (HSV-1) causes prevalent infections ranging from orolabial lesions to keratitis and encephalitis, with virus–host interplay around cell death pathways critically determining disease outcomes. This review systematically examines how HSV-1 dynamically manipulates programmed cell death processes-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-through multiple viral proteins to evade immune clearance, facilitate replication, or maintain latency. Concurrently, host DNA sensors such as AIM2 and IFI16 activate inflammasomes and the PANoptosome to trigger coordinated cell death that restricts viral spread; imbalances in this bidirectional regulation exacerbate tissue damage in skin, cornea, and central nervous system, driving neuroinflammation and blood-brain barrier disruption. Elucidating these mechanisms not only uncovers novel principles of HSV-1 pathogenesis and immune evasion but also informs antiviral therapies and the rational design of oncolytic HSV-1 vectors.
Tertiary lymphoid structure (TLS) correlates with improved prognosis in melanoma. The role of solute carrier family 52 member A2 (SLC52A2) in mediating this interplay and influencing melanoma progression remains unclear. Integrated bioinformatics analysis of melanoma datasets (GSE3189, GSE19234, GSE46801, GSE4587, GSE238207, GSE53223) were applied to identify TLS-associated candidate genes. Machine learning was performed to screen key genes validated in independent cohorts and clinical blood samples. In vitro functional assays and in vivo syngeneic models assessed the impact of SLC52A2 knockdown. TLS-related indicators were evaluated by immunohistochemistry, multiplex immunofluorescence (mIF), flow cytometry, and enzyme-linked immunosorbent assay. Furthermore, the downstream pathway of SLC52A2 was identified by bioinformatics analysis. CD8⁺ T cell depletion and pathway feedback experiments were conducted to validate mechanistic dependencies. Herein, SLC52A2 was identified as a key hub gene associated with TLSs. Silencing SLC52A2 significantly inhibited melanoma cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo, reducing Ki67 expression. SLC52A2 knockdown enhanced TLS formation, evidenced by increased CD4/CD20/CD68 infiltration, elevated CD3+/CD8+ T-cell infiltration with enhanced cytotoxic function (granzyme B⁺ and interferon-γ⁺), and upregulated TLS-organizing chemokines. mIF and quantitative TLS scoring confirmed significantly increased TLS abundance and maturity upon SLC52A2 silencing. Depletion of CD8⁺ T cells reversed both the TLS enhancement and the tumor-suppressive effects induced by SLC52A2 silencing. Mechanistically, interleukin (IL)− 17 signaling pathway was screened as the downstream pathway of SLC52A2. Experimentally, SLC52A2 knockdown reduced IL-17A/IL-17RA protein levels, and IL-17 receptor antagonist LY3509754 exhibited the anti-tumor role in vitro. Collectively, SLC52A2 drives melanoma progression by inhibiting TLS-mediated anti-tumor immunity and activating the IL-17 pathway, positioning SLC52A2 as a promising therapeutic target for melanoma.
Ferroptosis is a form of regulated cell death driven by labile iron-dependent lipid peroxidation and is closely integrated with cellular energy metabolism and redox homeostasis. Once viewed primarily as the terminal product of glycolysis, lactate is now recognized as a central metabolic intermediate, signaling molecule, and epigenetic substrate that reshapes intracellular and microenvironmental redox networks and thereby influences cell fate. Emerging evidence suggests that lactate exerts a context-dependent and bidirectional influence on the ferroptosis machinery. This regulation is mediated through four closely interconnected dimensions: lactate flux and concentration gradients, extracellular acidosis within the microenvironment, monocarboxylate transporter (MCT)-dependent transmembrane metabolic exchange, and site-specific histone and non-histone lactylation. This review systematically examines how lactate regulates ferroptosis in a context-dependent manner across different cell types, subcellular compartments, and disease microenvironments. In many tumors and stromal niches, lactate can act as a metabolic barrier that supports immunosuppression and ferroptosis resistance. By contrast, under specific stress conditions, dysregulated lactate flux may promote metabolic imbalance, epigenetic reprogramming, and increased ferroptotic vulnerability. We further summarize recent translational advances targeting the lactate-ferroptosis axis, including compartment-specific pharmacological strategies, emerging nanomedicine-based delivery platforms, and physical approaches for modulating the microenvironment. Although this framework provides a useful basis for therapeutic exploration, most current evidence remains preclinical. Rigorous validation in human tissues, patient-derived models, and early-phase clinical studies will be required before lactate-targeted ferroptosis strategies can be advanced toward precision therapy.
Acute kidney injury (AKI) is a common and severe clinical complication with limited treatment options. TRIM21, an E3 ubiquitin ligase, was previously shown to be upregulated in ischemia/reperfusion (I/R)-induced AKI. This study further revealed its role in DNA damage repair. Here, we demonstrated that TRIM21 expression is elevated in human kidney biopsies, murine AKI models, and injured renal tubular epithelial cells (TECs), in parallel with increased DNA double-strand breaks (DSBs). TRIM21 knockout attenuated renal injury, improved renal function, and decreased TECs apoptosis. Mechanistically, TRIM21 was found to bind to INTS3 and facilitate its proteasomal degradation, suppressing DNA repair and promoting apoptosis. INTS3 overexpression alleviated cisplatin-induced DNA damage and apoptosis in TECs. Through virtual screening and activity evaluation, SB33-0223 was identified as a small-molecule inhibitor targeting the C-terminal PRYSPRY domain of the TRIM21 protein. By blocking the recruitment of antibody-bound substrates, SB33-0223 effectively prevents TRIM21-mediated ubiquitination and degradation of INTS3, thereby enhancing INTS3 stability and reducing DNA damage in vitro and in vivo. Our study discovered SB33-0223 as an inhibitor of TRIM21 for the first time, highlighting the TRIM21/INTS3 axis as a critical regulator of DNA repair in AKI, supporting SB33-0223 as a promising lead for targeted therapeutic intervention.
Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.
Brain–heart syndrome (BHS) describes cardiac dysfunction secondary to central nervous system injury, with acute ischemic stroke (AIS) serving as a critical driver that exacerbates myocardial infarction (MI). This study aimed to elucidate the role of Apolipoprotein M (APOM) in stroke-aggravated MI and to explore its underlying systemic and molecular mechanisms. Clinical data were analyzed to evaluate the correlation between stroke and MI. A combined mouse model of middle cerebral artery occlusion (MCAO) and MI was established to assess neurological and cardiac injury. Quantitative proteomics and Weighted Gene Co-expression Network Analysis (WGCNA) were employed to screen key differentially expressed proteins. The role of APOM in myocardial injury was validated using APOM-knockout (KO) mice. Furthermore, nuclear-cytoplasmic fractionation, immunofluorescence, and Western blot were performed to investigate its effects on the Saa1 and NF-κB signaling, NLRP3-related inflammatory signaling pathway, and lipid metabolism pathways. Clinical analysis indicated that stroke is a significant risk factor for MI (OR = 4.5). In the mouse model, MCAO significantly exacerbated post-MI electrocardiographic abnormalities, myocardial inflammatory response, while elevating circulating levels of cTnT and IL-1β. Proteomics identified a significant downregulation of APOM in the heart, brain, and serum post-stroke, a trend consistent with observations in AIS patients. Further experiments revealed that APOM deficiency markedly worsened cardiac conduction disturbances, histological damage, and inflammatory responses in MI mice. Mechanistically, the loss of APOM upregulates the acute-phase protein Saa1, triggers NF-κB phosphorylation and nuclear translocation, and enhances inflammatory signaling related to inflammasomes, while simultaneously mediating cytokine release from cardiomyocytes. Concurrently, APOM deficiency led to a significant decrease in sphingosine-1-phosphate (S1P) and also caused myocardial lipid droplet accumulation and metabolite changes. Additionally, the loss of APOM increased the expression of D-dimer and fibrinogen family proteins. Our findings suggest that APOM is a potential cardioprotective agent post-AIS. Downregulation of APOM may exacerbate myocardial injury after MI by elevating Saa1 expression, activating the NF-κB pathway and the inflammasome-mediated signaling, and inducing lipid metabolic disorders and coagulation-associated alterations. APOM may represent a potential therapeutic target for the intervention of brain–heart syndrome.
KRAS mutations are among the most common genetic alterations in colorectal cancer (CRC) and are strongly linked to poor prognosis and therapeutic resistance. However, current treatments targeting KRAS-mutated CRC have shown limited clinical efficacy. Argonaute 2 (AGO2) is a critical component in microRNA (miRNA)-mediated gene silencing complex, which is involved in the maturation of miRNAs and the regulation of target genes. It has been reported that mutated KRAS can interact with AGO2 and impair its function, thereby amplifying the oncogenic potency of mutant KRAS and accelerating tumor progression. To explore the therapeutic implications of this interaction, we developed a peptide inhibitor and engineered peptide-gold nanoparticles (Au-pep) that specifically disrupted KRAS-AGO2 interaction, which dramatically attenuated the malignant phenotype of KRAS-mutated CRC cells. Mechanistically, Au-pep-mediated disruption of the KRAS-AGO2 complex led to partial restoration of the miRNA expression landscape, with let‑7c‑5p emerging as the most significantly up‑regulated effector. As a result, restored let-7c-5p caused a significant down-regulation of key oncogenic drivers (KRAS, c-Myc and Bcl2) to suppress the growth of KRAS-mutated CRC cells and induce their apoptosis. Furthermore, this miRNA restoration conferred dual therapeutic benefits by sensitizing KRAS-mutated CRC cells to 5-fluorouracil (5-FU) via ABCC5 repression and augmenting immunotherapy responsiveness via PD-L1 down-regulation. Our findings, taken together, delineate a new therapeutic paradigm with significant translational potential for improving clinical outcomes in this recalcitrant patient population.
Programmed cell death (PCD) is a central determinant of kidney injury, maladaptive repair, and chronic progression. Beyond classical apoptosis, the identification of ferroptosis, pyroptosis, and cuproptosis has expanded the conceptual framework of renal pathophysiology by linking cell fate decisions to redox imbalance, inflammatory signaling, mitochondrial metabolism, and metal ion homeostasis. Ferroptosis is driven by iron-dependent phospholipid peroxidation and impaired antioxidant defenses; pyroptosis is mediated by inflammasome activation, gasdermin pore formation, and cytokine release; apoptosis results from caspase-dependent cellular dismantling; and cuproptosis reflects copper-induced disruption of lipoylated tricarboxylic acid cycle proteins and mitochondrial proteostasis. Here, we propose a “metabolic crisis-cascade” framework, in which progressive disruption of energy metabolism, redox balance, and metal homeostasis acts as a unifying upstream mechanism linking multiple PCD pathways during kidney injury. In acute kidney injury (AKI), ferroptosis and pyroptosis contribute prominently to early tubular injury, whereas persistent apoptosis, recurrent ferroptotic stress, and emerging copper-dependent metabolic vulnerability contribute to chronic kidney disease (CKD), diabetic kidney disease, glomerular injury, inflammation, and fibrosis. These pathways are interconnected through common stress signals, including reactive oxygen species accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, Nrf2/Keap1-dependent antioxidant responses, inflammasome activation, and metal dysregulation. Understanding their temporal and compartment-specific activation is essential for distinguishing adaptive responses from irreversible damage. Targeting lipid peroxidation, inflammasome signaling, mitochondrial stability, apoptosis regulation, and copper metabolism may provide complementary strategies for limiting renal injury and preventing AKI-to-CKD transition. Future studies integrating multiomics approaches and disease-stage-resolved models will be required to define actionable cell-death signatures and enable precision interventions in kidney disease. Programmed cell death in kidney disease progression. The healthy kidney displays intact tubules and glomeruli. AKI is characterized by early ferroptosis, reflected by lipid peroxidation, and pyroptosis, reflected by cell swelling and cytokine release. CKD is characterized by tubular atrophy, fibrosis, recurrent ferroptotic stress, apoptosis, and emerging copper-dependent mitochondrial vulnerability.
Endometriosis (EMs) is characterized by the establishment and persistence of ectopic lesions, a process fundamentally dependent on aberrant angiogenesis. Endothelial cells (ECs) play a central role in this process; however, accumulating evidence indicates that ECs are not a homogeneous population but comprise multiple subtypes with distinct molecular signatures and functional states, including quiescent, proliferative, hormone-responsive and inflammation-associated phenotypes. The initiation and maintenance of pathological angiogenesis in EMs are coordinately regulated by hormonal signaling, inflammatory responses and immune modulation, which collectively determine vascular remodeling and lesion sustainability. Despite significant advances, mechanistic insights into EMs-associated angiogenesis have been limited by the lack of physiologically relevant experimental models. Conventional two-dimensional culture systems fail to recapitulate the complex three-dimensional cellular interactions, whereas animal models are constrained by interspecies differences. Recent progress in stem cell biology, extracellular matrix (ECM) engineering and microfluidic technologies has enabled the development of organoid-based platforms that more faithfully reconstruct the EMs microenvironment. When integrated with functional biomaterials possessing tunable mechanical properties and bioactivity, these systems allow precise modulation of endothelial behaviors, including proliferation, migration and lumen formation, through controlled delivery of angiogenic cues. In this Review, we summarize recent advances in biomaterial-supported organoid systems for dissecting endothelial cell heterogeneity and its contribution to aberrant angiogenesis in EMs. We further discuss their emerging roles in mechanistic studies and the development of targeted therapeutic strategies.
Resistance to apoptosis-targeted cancer therapies remains a major clinical hurdle. Ferroptosis, cuproptosis, and disulfidptosis represent typical forms of metabolic cell death that bypass classical apoptotic pathways, offering unprecedented opportunities to overcome such resistance. These three death modalities converge on a shared metabolic hub—the SLC7A11/cystine/GSH/NADPH axis—where disruption at different nodes steers the outcome toward ferroptosis, cuproptosis, or disulfidptosis. This interconnection is the foundation of our unified framework. While recent seminal reviews (Mao et al.) have established the conceptual framework integrating ferroptosis, cuproptosis, and disulfidptosis, the translational implementation of this framework remains fragmented. Here, we extend this established paradigm by providing a comprehensive, clinically actionable metabolic vulnerability atlas that not only systematically dissects the regulatory logic in both oncological and non-oncological settings but also, for the first time, proposes a bench-to-bedside bidirectional roadmap that prioritizes solutions for biomarker scarcity, systemic toxicity, and mechanistic heterogeneity. Crucially, we expand the framework to incorporate emerging modalities (e.g., oxeiptosis, alkalipoptosis), offering a dynamic extension to the static model. We systematically dissect their signaling networks, regulatory logic, and therapeutic strategies in both oncological and non-oncological settings. For the first time, we propose a translational research roadmap that identifies key bottlenecks across these pathways—including biomarker scarcity, systemic toxicity, and mechanistic heterogeneity—and prioritizes solutions tailored to each. Unlike existing reviews, our metabolic vulnerability atlas enables patient stratification and guides the rational design of selective modulators, supported by a bidirectional feedback loop between bench and bedside. By redefining metabolic cell death as a sabotage mechanism rather than an apoptotic process, this framework challenges the apoptosis-centric paradigm and provides a robust theoretical foundation for next-generation precision therapies that directly target the metabolic determinants of cell fate. These concepts are illustrated in an integrated schematic (Fig. 1), which sets the stage for the mechanistic and therapeutic analyses that follow.
Induction of programmed cancer cell death by selective aryl hydrocarbon receptor (AHR) ligands represents a promising strategy for developing novel anticancer therapeutics. In this study, we characterized the anticancer activity and underlying mechanism of the selective AHR ligand CGS-15943 in lung cancer cells. CGS-15943 potently inhibited the growth of lung cancer cell lines expressing high levels of AHR, whereas CRISPR-mediated knockout of AHR in H460 and H69AR cells markedly rescued cells from CGS-15943-induced cell death, demonstrating an essential role for AHR. To identify additional mediators of this response, we performed a genome-wide CRISPR knockout screen, which revealed eight enzymes involved in the heme biosynthesis pathway, three heme-containing enzymes, as well as AHR and its transcriptional partner ARNT, as critical determinants of CGS-15943-induced cell death. Transcriptomic analyses further showed that CGS-15943 induced AHR-dependent transcriptional programs enriched for oxidative stress and oxidized phospholipid response pathways. Together, these findings identify key components of the AHR signaling network that regulate a programmed heme-dependent cell death pathway and establish CGS-15943 as a promising lead compound for targeting AHR-positive lung cancers.
Programmed cell death represents a fundamental process in maintaining organismal homeostasis and responding to pathological challenges. The traditional view considered apoptosis, pyroptosis, and necroptosis as independent death pathways. However, recent research has revealed extensive interactions and synergies among these pathways, leading to the emergence of a novel form of cell death termed "PANoptosis." Triggered by specific stimuli, PANoptosis involves the assembly of a large multiprotein complex called the PANoptosome. This complex integrates key molecules and morphological features from apoptosis, pyroptosis, and necroptosis, culminating in a highly efficient and coordinated inflammatory cell death program. Concurrently, non-coding RNAs, as crucial regulators of gene expression, participate extensively in the regulation of cellular fate at the post-transcriptional and epigenetic levels. This review systematically summarizes the molecular mechanisms by which non-coding RNAs regulate the core components of PANoptosis and its upstream signaling pathways. It further delves into the pathological role of this regulatory axis in infectious diseases, cancer, neurodegenerative disorders, and autoimmune diseases. Additionally, the article explores the diagnostic potential of non-coding RNA-based approaches and therapeutic strategies targeting the non-coding RNA-PANoptosis axis, while also addressing current challenges related to mechanistic complexity, delivery technologies, and safety assessment. This review aims to establish a systematic framework for the "non-coding RNA-PANoptosis-disease" regulatory axis, providing a theoretical basis for understanding the interactive logic of cell death networks and for developing precise interventions for related diseases.
Inflammatory activation is involved in the pathogenesis of heart failure (HF). ATPase H+-Transporting Accessory Protein 2 (ATP6AP2) is an auxiliary subunit of the V-ATPase, and its role in HF is not fully understood. To assess the role and regulatory mechanisms and therapeutic potential of ATP6AP2 in HF, we used a cardiac-specific ATP6AP2 conditional knockout (CKO) mouse model and observed spontaneous cardiac dysfunction, myocardial fibrosis and cardiomyocyte apoptosis in mice. Further studies showed that ATP6AP2 promoted stimulator of interferon genes (STING) degradation through the lysosome-dependent pathway. ATP6AP2 knockdown significantly upregulated STING protein levels, activated the STING-TBK1-IRF3 signaling axis, and promoted pro-inflammatory factor expression and cardiomyocyte apoptosis. In mice with myocardial infarction (MI), myocardial overexpression of ATP6AP2 or treatment with H-151 inhibited the activation of the STING signaling pathway, ameliorated cardiomyocyte apoptosis and inflammatory responses, thereby improving cardiac function. In addition, in macrophages treated with conditioned medium from hypoxia-exposed cardiomyocytes, the levels of pyroptosis-related proteins were markedly increased, whereas ATP6AP2 overexpression or STING inhibition reduced pyroptosis. ATP6AP2 likewise attenuates inflammation and pyroptosis caused by hypoxia in cardiac organoids. In conclusion, activating ATP6AP2 could serve as a promising therapeutic option in HF.
A landmark 2026 Cell publication by Chai et al. characterized Ruptosis, a previously unclassified form of regulated cell death executed by specialized glandular immune cells termed ruptoblasts in the planarian Schmidtea mediterranea. Triggered exclusively by elevated activin (a dual hormone/inflammatory cytokine), Ruptosis manifests rapid, contact-independent explosive cellular disintegration and releases diffusible toxins to eliminate aberrant somatic cells, stem cells and invading bacteria. Distinct from apoptosis, pyroptosis, necroptosis, ferroptosis and neutrophil NETosis at morphological, biochemical and kinetic levels, this novel lytic pathway substantially expands the canonical regulated cell death (RCD) classification system. This commentary outlines the defining unique features of Ruptosis and discusses its evolutionary implications for cell death and innate immunity research.
Lung ischemia–reperfusion injury (IRI), a significant factor contributing to early mortality following lung transplantation (LTx), is driven by molecular mechanisms that are not yet fully understood. In this study, we elucidate a crucial signaling pathway initiated by extracellular histones (ex-His), which connects mitochondrial damage to inflammatory cell death. Through the use of a murine model of lung IRI and in vitro experiments with alveolar macrophages, we demonstrate that ex-His facilitate Drp1-dependent mitochondrial fission, resulting in the release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Our mechanistic analysis reveals that cytosolic ox-mtDNA is detected by the transcription factor IRF1, which subsequently upregulates NLRC5 at the transcriptional level. Additionally, we identify NLRC5 as a non-canonical scaffold that is essential for the assembly of the PANoptosome, a multi-protein complex that mediates PANoptosis, an inflammatory cell death pathway that aggravates tissue damage. The clinical relevance of this pathway was then examined in lung transplant recipients. An analysis of their peripheral blood mononuclear cells (PBMCs) revealed that patients who developed primary graft dysfunction (PGD) exhibited markedly elevated levels of circulating histones and cytosolic ox-mtDNA. This was associated with hyperactivation of the core signaling axis, characterized by increased Drp1 phosphorylation and elevated expression of IRF1 and NLRC5. Collectively, our study elucidates a comprehensive pathogenic cascade from an extracellular danger signal to a specific cell death program, identifying the ex-His-mitochondria-IRF1-NLRC5 axis as a critical driver of macrophage PANoptosis and a promising therapeutic target for alleviating lung IRI.
