Ischemic stroke (IS), the most prevalent type of stroke worldwide, is associated with a variety of complex processes, including oxidative stress, apoptosis, and ferroptosis. Recent findings indicate that inhibiting iron overload as a key regulatory mechanism of ferroptosis profoundly influences the pathogenesis and treatment of IS. In addition, enhanced blood-brain barrier (BBB) penetration and precise targeting of the ischaemic site contribute to improved therapeutic outcomes in IS. In this study, we developed FeSO4 templated-molecularly imprinted nanoparticles (MINPs) with high-affinity recognition of ferrous ions (Fe2+). MINPs exhibited physicochemical properties that perfectly match the polarity and condensed structure of Fe2+, resulting in the effective and specific clearance of Fe2+ through efficient and selective adsorption both in vivo and in vitro. Moreover, MINPs hitchhiked circulating neutrophils, thereby facilitating their penetration through BBB and enhancing targeted delivery to the ischemic brain. Our results, supported by transcriptomic analysis, further elucidated the molecular mechanisms by which MINPs significantly inhibit ferroptosis while concurrently regulating apoptosis and inflammation, thereby conferring marked neuroprotection against IS.

Radiotherapy represents a conventional approach in clinical cancer treatment, but suffers from insufficient DNA damage and limited tumor selectivity. Herein, bismuth oxyiodide quantum dots loaded hollow manganese dioxide (MB) nanoparticles was fabricated and subsequently wrapped with bacterial membrane vesicles (MVs) to create MB@MV nanoparticles. This biomimetic radiosensitizer is designed to enhance the efficacy of radiotherapy through a combined approach of tumor immunotherapy and oxygen delivery strategy. Upon systemic administration, MB@MV enhance tumor accumulation through specifically targeting the inflammatory milieu mediated by MVs, thereby activating dendritic cell-mediated innate immunotherapy. Concurrently, MB@MV demonstrate superior X-ray absorption, leading to effective DNA damage in tumor cells due to the high atomic number of bismuth. Notably, manganese dioxide react with the overexpressed H2O2 in the tumor microenvironment to alleviate hypoxia and fixing X-ray induced DNA damage in tumor cells, culminating in a multi-strategy approach to enhance radiotherapy sensitization. The findings from both in vitro and in vivo experiments demonstrate a significantly enhanced inhibition of tumor growth by MB@MV compared to tumors treated solely with X-ray. Overall, our multifunctional radiosensitizer MB@MV shows considerable promise in the field of tumor radiotherapy.

Dry eye disease (DED) is a common ocular surface problem. Ocular surface inflammation and oxidative stress triggered by increased tear osmolarity are crucial pathogeneses of DED. Oroxylin A (OA) extracted from Scutellaria baicalensis exhibits anti-inflammatory, antioxidant, and cell protective properties. The aim of this study was to determine the protective effect and explore the potential mechanisms of OA on hyperosmotic stress-induced human corneal epithelial cells (HCECs). In this study, we demonstrated that OA exhibited a marked protective effect on hyperosmolarity-induced HCEC damage, including improving cell viability and decreasing lactate dehydrogenase release. Furthermore, OA reduced the expression of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and the generation of oxidative stress-related markers (ROS and NO) in hyperosmotic stress-induced HCECs. In addition, OA decreased HCEC pyroptosis by decreasing NLRP3, caspase-1, cleaved-caspase-1, and N-GSDMD levels. OA also decreased HCEC apoptosis by enhancing Bcl-2 expression while simultaneously decreasing caspase-3 and Bax levels. Moreover, OA enhanced SIRT3 expression in hyperosmotic stress-induced HCECs. A SIRT3 inhibitor reversed the alleviation of pyroptosis and apoptosis induced by OA. SIRT3 could promote SOD2 expression and inhibit HIF-1α and ROS expression in hyperosmotic stress-induced HCECs. In conclusion, OA exhibits anti-inflammatory and antioxidant properties and can alleviate the pyroptosis and apoptosis of HCECs under hyperosmotic stimulation by activating the SIRT3-SOD2/HIF-1α signaling pathway. Therefore, OA may be a new treatment target for dry eye disease.

Neurodegenerative diseases comprise a group of central nervous system disorders marked by progressive neuronal degeneration and dysfunction. Their pathogenesis is multifactorial, involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Recent research has highlighted the potential of exercise as a non-pharmacological intervention for both the prevention and treatment of these disorders. In particular, exercise has received growing attention for its capacity to upregulate the expression and activity of SIRT1, a critical mediator of neuroprotection via downstream signaling pathways. SIRT1, a key member of the Sirtuin family, is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. It plays an essential role in regulating cellular metabolism, energy homeostasis, gene expression, and cellular longevity. In the context of neurodegenerative diseases, SIRT1 confers neuroprotection by modulating multiple signaling cascades through deacetylation, suppressing neuronal apoptosis, and promoting neural repair and regeneration. Exercise enhances SIRT1 expression and activity by increasing NAD + synthesis and utilization, improving intracellular redox balance, alleviating oxidative stress-induced inhibition of SIRT1, and thereby promoting its activation. Moreover, exercise may indirectly modulate SIRT1 function by influencing interacting molecular networks. This review summarizes recent advances in the therapeutic application of exercise for neurodegenerative diseases, with a focus on SIRT1 as a central mechanism. It examines how exercise mediates neuroprotection through the regulation of SIRT1 and its associated molecular mechanisms and signaling pathways. Finally, the paper discusses the potential applications and challenges of integrating exercise and SIRT1-targeted strategies in the management of neurodegenerative diseases, offering novel perspectives for the development of innovative treatments and improvements in patients' quality of life.

In situ vaccination (ISV) strategies offer an innovative approach to cancer immunotherapy by utilizing drug combinations directly at tumor sites to elicit personalized immune responses. Tumor cell-derived extracellular vesicles (TEVs) in ISV have great potential but face challenges such as low release rates and immunosuppressive proteins like programmed death ligand 1 (PD-L1) and CD47. This study develops a nanoparticle-based ISV strategy (Combo-NPs@shGNE) that enhances TEV release and modulates cargo composition. This approach combines Andrographolide, Icariside II, and shRNA targeting UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), which accumulates in the tumor region, resulting in the regulation of immunosuppressive pathways and the reduction of sialic acid production. Decreasing the level of sialylation on the membrane through necroptosis and inhibition of sialic acid synthesis decreased the loading of PD-L1 and CD47 on vesicles, while increasing the loading of heat shock protein 70 and high mobility group box 1 on vesicles, and induced the release of highly immunogenic TEVs from the cancer cells, with a 56.44 % release, 9.57 times higher than that of blank nanoparticle-treated cells. In vivo studies demonstrate that Combo-NPs@shGNE enhances TEV yield, tumor growth, reduces metastases, and improves survival in an osteosarcoma mouse model. It promotes dendritic cell maturation, increases CD4+ and CD8+ T cell infiltration, and alters the microenvironment by reducing myeloid-derived suppressor cells and enhancing immunostimulatory factors. Additionally, it transitions tumor-associated macrophages from M2 to an M1 phenotype, thereby augmenting tumor immunity. Overall, Combo-NPs@shGNE offers a promising method for transforming tumors into personalized autologous vaccines, potentially advancing cancer treatment strategies.

Oral squamous cell carcinoma (OSCC) is characterized by poor prognosis and high mortality. Understanding programmed cell death-related genes could provide valuable insights into disease progression and treatment strategies.

RNA-sequencing data from 341 OSCC tumor tissues and 31 healthy samples were analyzed from TCGA database, with validation using 76 samples from GSE41613. Single-cell RNA sequencing data was obtained from GSE172577 (6 OSCC samples). Differentially expressed genes (DEGs) were identified and intersected with 1,254 programmed cell death-related genes. A protein-protein interaction network was constructed, and key modules were identified. Univariate Cox, LASSO, and multivariate Cox regression analyses were performed to build a prognostic model. Model performance was evaluated using Kaplan-Meier analysis, ROC curves, and nomogram validation.

The study identified 200 candidate genes from the intersection of DEGs and programmed cell death-related genes, which were further refined to 57 hub genes through PPI network analysis. A prognostic signature consisting of five genes (MET, GSDMB, KIT, PRKAG3, and CDKN2A) was established and validated. The model demonstrated good predictive performance in both training and validation cohorts (AUC > 0.6 for 1-, 2-, and 3-year survival). Single-cell analysis revealed that prognostic genes were predominantly expressed in stromal and epithelial cells. Cell communication analysis indicated strong interactions between stromal and epithelial cells.

This study developed and validated a novel five-gene prognostic signature for OSCC based on programmed cell death-related genes. The model shows promising clinical application potential for risk stratification and personalized treatment of OSCC patients.

Neodymium, as a strategic rare earth element (REE), has demonstrated bioaccumulative potential and can permeate human systems through inhalation of airborne particulates, ingestion of contaminated food/water, and dermal absorption from soil matrices, ultimately eliciting multi-organ toxicological manifestations. However, the hepatotoxicological profile of neodymium species and their pathophysiological mechanisms remain inadequately characterized. Neodymium nitrate (Nd(NO3)3), the predominant water-soluble neodymium species, exhibits marked bioavailability with particular hepatic tropism.

This study aims to investigate the effects of neodymium nitrate on apoptosis of mouse liver cells and its underlying molecular mechanisms.

Mouse liver cell line AML12 was treated with gradient concentrations of neodymium nitrate. The results showed that neodymium nitrate inhibited liver cell proliferation, induced apoptosis, and exhibited a dose-dependent relationship. Western blotting and quantitative real-time PCR (qRT-PCR) revealed that neodymium nitrate suppressed Bcl2l1 transcription and activated the proteolysis of Caspase 3. To further explore the molecular mechanism, Bcl2l1 protein was overexpressed in mouse liver cells. The findings indicated that overexpression of Bcl2l1 rescued neodymium nitrate-induced apoptotic phenotypes and attenuated Caspase 3 cleavage.

The present data suggest that neodymium nitrate induces apoptosis of mouse liver cells through the Bcl2l1/Caspase 3 pathway. However, further studies are called for to substantiate this view, as the findings may provide critical mechanistic evidence for revising the toxicological risk assessment frameworks of rare earth elements.

Poor bioavailability and dose-limiting cardiotoxicity persistently hinder the clinical application of bufalin (BF). Conventional BF-based nanoagents have shown promise in tackling these challenges, yet advanced nanostrategies with further improved performance and clinical accessibility still await development. Herein, we introduce a novel cooperative nanoparadigm based on disulfide-linked BF homodimeric prodrugs (SBF) and metal-phenolic networks (MPNs). This strategy achieves high drug-loading capacity and structural stability. Stability perturbation experiments reveal that hydrophobic interactions, electrostatic adsorption, and coordination bonds synergistically drive co-assembly of SBF and MPNs. The resultant nanopartieles (MSBNAs) exhibit prolonged circulation kinetics, tumor-selective accumulation, and pH/GSH dual-responsive properties, effectively mitigating BF-induced cardiotoxicity. Further antitumor mechanistic investigations unveil that MSBNAs amplify BF-induced ferroptosis through a dual assault of oxidative stress and iron overload induced jointly by MPNs-delivered exogenous iron and BF-triggered endogenous iron. This increased ferroptosis endows MSBNAs with superior suppression of tumor growth and lung metastasis, maintaining excellent biocompatibility without cardiotoxicity. Our work not only establishes a promising candidate platform to surmount the therapeutic hurdles of BF but also enriches the design landscapes of co-assembled nanomedicines, thereby laying a foundation for the clinical translation of BF and other antitumor drugs.

Ferroptosis has been implicated in several reproductive disorders, but the underlying mechanisms remain unknown; thus, interventions targeting this pathway are lacking. Here we summarize the emerging findings on ferroptosis in reproductive biology and corresponding disorders, and highlight perspectives and challenges on future ferroptosis research with potential clinical applications.

Bisphenol S (BPS), as an environmental pollutant, is known to reduce brain lipid levels and induce neurotoxicity. However, whether brain lipid imbalance can induce neurotoxicity has not yet been clarified. Here, wild-type zebrafish and apoEb mutant zebrafish were used to investigate the effect of BPS on the macrophages proliferation and microglia mobilization caused by the decrease of cerebral lipids and its potential neurotoxic effects. The zebrafish exposed to BPS (1, 10, or 100 μg/L) from 2 hours after fertilization (hpf) to 3 days after fertilization (dpf) displayed microglial aggregation, as well as a decrease in brain lipid content. Lipidomic analyses of the brains and plasma of 50 dpf zebrafish exposed to BPS were used to identify key lipids, including lysophosphatidylcholine and phosphatidylcholine in brain and phosphatidylcholine in plasma. The apoEb mutant zebrafish as a hyperlipidemia model was used to further demonstrate that BPS-induced lipid reduction increased the number of microglia in the brain. Our data provide new insight into the mechanism by which pollutants cause neurotoxicity.

In mammals, caspase 8 (CASP8) is a well-known initiator caspase of apoptosis. In invertebrates, the function of CASP8 is poorly understood. Herein, we examined the function of abalone Haliotis discus CASP8 (HdCASP8). Compared to mammalian CASP8, HdCASP8 possesses the conserved DED and CASc domains but also has an extra death domain (DD). HdCASP8 induced marked apoptosis of HEK293T cells without activating CASP3/6/7. Consistently, HdCASP8 did not cleave H. discus CASP3 (HdCASP3). HdCASP8 exhibited CASP3/6-like cleavage specificity and cleaved the apoptotic substrate DFF45. HdCASP3 is known to activate abalone pyroptosis by cleaving H. discus gasdermin E (HdGSDME) at two sites, DQVD and DEID. In the present work, HdCASP8 was found to interact with HdGSDME at its C-terminal region and induce pyroptosis by cleaving HdGSDME at DQVD but not at DEID. During bacterial infection, the expressions of HdCASP8 and HdGSDME were significantly upregulated in multiple tissues of abalone in a time-dependent manner. Together these results indicate that, most likely owing to its unique structural feature, HdCASP8 differs from the classical CASP8 by acting as an apoptosis/pyroptosis-regulating CASP3 and from the classical CASP3 in certain aspects of substrate specificity. These findings provide new insights into CASP8-mediated programmed cell death in invertebrates.

Atrazine (ATZ) and diaminochlorotriazine (DACT) accumulation poses liver health risks in animals and humans. Lycopene (LYC), a carotenoid found in red plants and fruits, exhibits potent antioxidant effects. This study explores the interaction between LYC and ATZ in mouse hepatocyte ferroptosis and the potential regulatory role of Cytochrome P450 oxidoreductase (CYPOR) in this process. Male mice were exposed to ATZ (50 mg/kg or 200 mg/kg) and/or LYC (5 mg/kg) by gavage for 21 days. In vitro experiments, a mouse hepatocyte cell line (AML12) was exposed to DACT (200 μM) and/or LYC (2 μM) for 12 h with or without small interfering RNA treatment. We found that both ATZ and DACT promoted CYPOR expression and caused liver injury. ATZ/DACT promotes Fe2+ accumulation and lipid peroxidation, ultimately leading to Ferroptosis in mouse hepatocytes. However, LYC alleviated ATZ/DACT-induced Ferroptosis by inhibiting CYPOR. The CYPOR knockdown resulted in the blockage of ATZ/DACT-induced ferroptosis, while the alleviation of ferroptosis by LYC was further enhanced. Thus, CYPOR can regulate ferroptosis in mouse hepatocytes and is a novel target for the treatment of hepatocyte ferroptosis-related diseases. Lycopene can be used as a functional dietary supplement to scavenge ferroptosis and reduce chronic liver disease.

Triple-negative breast cancer (TNBC) has no expression on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), resulting in an ineffective treatment using current therapeutic therapies. As a heterogeneous disease, the notable refractory, high recurrence rate and unfavorable prognosis facilitate some researches to further elaborate novel insights into the biology of TNBC and formulate the precision treatment. Ferroptosis is a unique regulated-cell-death modality characterized by the excessive accumulation of the lipid peroxides on cellular membranes in an iron-dependent manner. Resveratrol (RES), a natural antioxidant that possesses biological activities, has various potential benefits for many diseases through regulating the cell activity. RES has been reported to markedly inhibit the tumor progression, yet its role in ferroptosis pathway of TNBC and the underlying mechanism remain unclear. In this study, we found that RES suppressed cell viabilities, consisting of cell migration, cell colony formation, and induced the cell apoptosis, along with mitochondrial structure damage, intracellular iron overload, increasing reactive oxygen species (ROS) and lipid peroxidation accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion, interestingly, which was reversed by ferroptosis inhibitors. Next, the protein level of GPX4 was significantly suppressed in RES-treated TNBC cells in vitro and in vivo, facilitating the cancer cell ferroptosis. Our data confirm that RES suppresses GPX4 protein by increasing the NEDD4L-mediated ubiquitination attributed from the enhanced interactions between NEDD4L and GPX4 through the inhibition of the ERK1/2/SGK1/NEDD4L/GPX4 pathway in vitro and in vivo. In conclusion, our study identified the mechanism by which RES could exert ferroptosis in TNBC, finally providing a novel strategy for TNBC treatment.

Kidney diseases, characterized by renal dysfunction, are the leading causes of death worldwide. It is crucial to prevent and treat kidney diseases to reduce their associated morbidity and mortality. Moderate physical exercise has been recognized to be advantageous for kidney health. Irisin is an exercise-induced myokine that was identified in 2012. It plays an important role in energy and bone metabolism, oxidative stress reduction, anti-inflammatory processes, cell death inhibition, and cardiovascular protection. However, the relationship between irisin and kidney diseases have not been fully elucidated. This review explores the role of irisin as a biomarker for kidney disease diagnosis and its associated complications, as well as the mechanisms through which it participates in various cell death pathways, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, irisin secretion levels were discussed to provide a basis for kidney disease prevention and treatment avenues, as well as therapeutic guidance for developing new and promising intervention strategies. Clinical Trial Registration: None.

Osteonecrosis of the femoral head (ONFH) is a severe disease characterized by bone tissue necrosis due to vascular impairment, often leading to joint collapse and requiring surgical intervention. Extracellular vesicles (EVs) serve as crucial mediators of intercellular communication, influencing osteogenesis, angiogenesis, and immune regulation. This review summarizes the dual role of EVs in both the pathogenesis of ONFH and post-necrosis bone repair, highlighting the impact of various EV-mediated signaling pathways on bone regeneration and the potential crosstalk among these pathways. Additionally, EVs hold promise as diagnostic biomarkers or contrast agents to complement conventional imaging techniques for ONFH detection. By elucidating the role of EVs in osteonecrosis and addressing the current challenges, we aspire to establish a foundation for the timely identification and treatment of ONFH. The translational potential of this article: This review comprehensively discusses the role of EVs in ONFH, providing innovative and promising insights for its diagnosis and treatment, which also establishes a theoretical foundation for the future clinical application of EVs in ONFH.

Chemodynamic treatment (CDT) possesses the ability to disturb intracellular redox equilibrium, thus inhibiting tumor development. The copper-induced CDT generally needs the delivery of copper (II) ions to tumor cells and reacting with local GSH, to produce Cu+, and thus generating toxic hydroxyl radicals (·OH) via a Fenton-like reaction. Due to an insufficient amount of endogenous GSH, it remains a great challenge to achieve satisfactory anticancer efficacy and the development of a receptor with the capability of both binding and reducing Cu (II) ions is valuable. In this study, we synthesized a novel amphiphilic diacylhydrazone (compound 1) by a brief chemical reaction. Compound 1 was not only capable of complexation with copper(II) ions but able to reduce the divalent copper ions partially to the monovalent ones. The generated assembly (complex 1) containing mixed Cu (I)/Cu (II) presents a spherical-like nanoparticle, which could easily enter the HCT-116 cells and release both Cu+ and Cu2+ in a mildly acidic environment. The complex 1 therefore inhibited the growth of HCT-116 cells due to the mitochondrial damage initiated by the enhanced Fenton-like effect and the growth inhibition rate of in vivo colon cancer proliferation reached 85.12 %, significantly higher than that of its components of either compound 1 or Cu(ClO4)2, as well as paclitaxel (the positive control). Meanwhile, complex 1 had relatively low toxicity. This work provided a reference for transit Cu (I/II)-mediated precision-targeted CDT therapeutic regimen.

In recent years, the abuse of ketamine as a recreational drug has been growing, and has become one of the most widely abused drugs. Continuous using ketamine poses a risk of drug addiction and complications such as attention deficit disorder, memory loss and cognitive decline. Ketamine-induced neurotoxicity is thought to play a key role in the development of these neurological complications. In this paper, we focus on the molecular mechanisms of ketamine-induced neurotoxicity. According to our analyses, drugs in causing neurotoxicity are closely associated with programmed cell death (PCD) such as apoptosis, autophagy, necroptosis, pyroptosis, and Ferroptosis. Therefore, this review will collate the existing mechanisms of programmed death in ketamine-induced neurotoxicity as well as explore the possible mechanisms by outlining the mechanisms of programmed death in other drug-induced neurotoxicity, which may be helpful in identifying potential therapeutic targets for neurotoxicity induced by ketamine abuse.

Cancer research takes a long time and is complex. Preclinical studies prove that compounds can be potential anticancer agents and contribute to cancer studies. Overexpression of survivin may cause decreased sensitivity of anticancer agents and antiapoptotic activation through its excretion from cells via MDR. Anthraquinones and phosphazene compounds, which are among the active biological compounds and identified in many studies on cancer, come to the fore in biochemical, microbiological, and pharmacological studies. In this study, it was aimed to investigate the effect of 2-hydroxyanthraquinone-substituted spiro-/ansa cyclotriphosphazene compounds (II-VIII) on multidrug resistance, ER stress, and apoptotic cell death pathways in breast and colon cancer cells. mRNA expressions of multidrug resistance transporter, ER stress, heat shock, and apoptotic genes assessed by qPCR. Besides protein levels of apoptosis, cell cycle and related signaling pathways (CASP3, BCL-w, sTNF-R, cIAP-2, TRAILRs, IGFBPs, Survivin, XIAP, etc.) were determined by antibody membrane array method in MCF-7 and DLD-1 cell lines. To elucidate the activities of Survivin protein-related compounds, in silico-mediated molecular docking studies were evaluated. ABCs, HSPs, and GRPs gene expressions in MCF-7 and DLD-1 cells were decreased by these compounds. Besides, in gene regulations of apoptosis and signaling pathways, it was observed that the compounds induce overexpression of BAX and underexpression BCL-2. In addition, especially survivin expression was downregulated by all the compounds. It has been determined that the compounds eliminate multidrug resistance in breast and colon cancer cells, suppress HSPs and GRPs genes, and lead the cells to death, especially through the antiapoptotic pathway Survivin. These compounds can be evaluated and developed as Survivin inhibitor agents in anticancer studies.

Receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, has emerged as an important target for therapeutic intervention. Flavonoids are natural compounds known for their anti-inflammatory and antioxidant properties, with recent studies highlighting their potential to modulate necroptosis. In this study, we explored the potential of RIPK3 as a target for flavonoids to achieve anti-necroptosis and anti-inflammatory effects. A library of 63 flavonoids was tested for RIPK3 binding and kinase inhibition using fluorescence polarization (FP) competition assay and ADP-Glo kinase activity assay. Six flavonoids, including scutellarein, robinetin, baicalin, myricetin, baicalein, and tricetin, showed significant inhibition of RIPK3, with IC50 values ranging from 2.5 to 13.7 μM. Structural studies of tricetin and robinetin through co-crystallization and molecular docking revealed distinct binding modes of these flavonoids within the ATP-binding pocket of RIPK3. The anti-necroptosis effects of these flavonoids were further evaluated in human HT-29 cells and mouse embryonic fibroblasts (MEFs) using a TSZ-induced cell death assay, resulting in EC50 values in the tens of micromolar range. Western blot analysis demonstrated that these flavonoids inhibit the phosphorylation of RIPK3 and its downstream effector, mixed lineage kinase domain-like protein (MLKL), and disrupt the formation of RIPK1 and RIPK3 aggregates in the necroptosis pathway. These findings identify RIPK3 as a target of natural flavonoids for the first time and elucidate the molecular mechanism underlying the anti-necroptotic activity of these flavonoids.

Escape from apoptosis is one of the main hallmarks of cancer. The imbalance of BCL-2 family members is a key factor leading to radiotherapy resistance. Targeting BCL-2 can overcome radiotherapy resistance by promoting apoptosis. Nevertheless, the function of BCL-2 in regulating the tumor immune microenvironment (TIME) is still not well understood. Herein, we discovered that the specific BCL-2 inhibitor sonrotoclax (BGB-11417) boosted the effectiveness of radiotherapy in an immune-mediated manner. Using flow cytometry, we found that sonrotoclax combined with radiotherapy polarized tumor-associated macrophages (TAMs) toward the M1-type and promoted the infiltration of Gzmb+ CD8+ T cells into the tumor. Mechanistically, we demonstrated that the combination of sonrotoclax and radiotherapy induced immunogenic ferroptosis of cancer cells by inhibiting GPX4 expression, released tumor-associated damage-associated molecular patterns (DAMPs) and subsequently activated the NF-κB pathway in TAMs. Moreover, the combination therapy also led to aberrant cytosolic DNA abundance and activated the cGAS-STING pathway in cancer cells, leading to the release of type I interferons and enhanced activation of CD8+ T cells. Meanwhile, the activation of cGAS-STING pathway also led to the upregulation of PD-L1 expression. Further combination of sonrotoclax and radiotherapy plus anti-PD-L1 exerted the most significant anti-tumor effects. Overall, our study indicated that sonrotoclax enhanced the anti-tumor immune response of radiotherapy through non-apoptotic roles of BCL-2, and shed light on the further clinical evaluation of the triple combination therapy of sonrotoclax, radiotherapy and immunotherapy.

Pyroptosis is a distinct form of cell death that plays a critical role in intensifying inflammatory responses. It primarily occurs via the classical pathway, non-classical pathway, caspase-3/6/7/8/9-mediated pathways, and granzyme-mediated pathways. Key effector proteins involved in the pyroptosis process include gasdermin family proteins and pannexin-1 protein. Pyroptosis is intricately linked to the onset and progression of non-alcoholic steatohepatitis (NASH). During the development of NASH, factors such as pyroptosis, innate immunity, lipotoxicity, endoplasmic reticulum stress, and gut microbiota imbalance interact and interweave, collectively driving disease progression. This review analyzes the molecular mechanisms of pyroptosis and its role in the pathogenesis of NASH. Furthermore, it explores potential diagnostic and therapeutic strategies targeting pyroptosis, offering new avenues for improving the diagnosis and treatment of NASH.

Disulfidptosis, a regulated cell death modality driven by the cystine transporter solute carrier family 7 member 11 (SLC7A11), is characterized by actin cytoskeleton collapse under glucose starvation. This review systematically elucidates the pivotal role of disulfidptosis in tumor metabolic reprogramming, with a focus on its molecular mechanisms and distinctions from other cell death pathways. The core mechanisms include SLC7A11-mediated cystine overload and NRF2/c-Myc-regulated pentose phosphate pathway activation. By integrating multiomics data and single-cell transcriptomics, we comprehensively decipher the heterogeneous expression patterns of disulfidptosis-related genes (DRGs) and their dynamic interplay with immune microenvironment remodeling. Furthermore, the coexpression networks of DRGs and disulfidptosis-related long noncoding RNAs (DRLs) offer novel insights into tumor diagnosis, prognosis, and targeted therapy. Therapeutically, SLC7A11 inhibitors (e.g., HG106) and glucose transporter inhibitors (e.g., BAY-876) demonstrate efficacy by exploiting metabolic vulnerabilities, whereas natural compounds synergizing with immune checkpoint blockade provide strategies to counteract immunosuppressive microenvironments. Through interdisciplinary collaboration and clinical translation, disulfidptosis research holds transformative potential in redefining precision oncology.

Garpedvinin A (1), a novel polycyclic polyprenylated acylphloroglucinol (PPAP) with a bicyclo[4,2,1]nonane core, 13 previously undescribed PPAPs, garpedvinins B-N (2-14) and 6 known analogs (15-20) were isolated from Garcinia pedunculata by various chromatographic methods combined with Global Natural Products Social Molecular Networking. The structures were identified by the analyses of spectral characteristics, computational chemistry calculations and single-crystal X-ray diffraction. A plausible biosynthetic pathway for garpedvinin A was suggested based on the isolated precursor, cambogin. Compounds 2-6, 8, 11, 13, 15-18 and 20 displayed cytotoxic effects on three cancer cell lines, HepG2, A549 and MCF-7. 6 showed the strong inhibitory effect on the proliferation of HepG2 cells in vitro, inducing cell apoptosis in a concentration-dependent manner and blocking the cell cycle at the S phase. Furthermore, 6 affected the expression of apoptosis-related proteins Bax, Bcl2 and pro-Caspase-3.

Annexin A2 (ANXA2) is a multifunctional protein that binds to calcium and phospholipids and plays a critical role in various pathological conditions, including cancer and inflammation. Recently, there has been increasing recognition of the significant role of ANXA2 in inhibiting apoptosis and promoting immune evasion in tumour cells. Therefore, a deep understanding of the regulatory mechanisms of ANXA2 in tumour cell apoptosis and its relationship with immune evasion can provide new targets for cancer therapy. This review summarizes the role and mechanisms of ANXA2 in regulating apoptosis in tumour cells, the connection between apoptosis regulation and tumour immunity, and the potential role of ANXA2 in therapy resistance.

Synthetic phenolic antioxidants (SPAs) are the most widely used antioxidants in the world. There is a growing concern due to their potential toxic effects and high pollution levels in aquatic environments. Existing studies have confirmed the neurotoxic, immunotoxic, and developmental toxicity of SPAs on aquatic organisms. However, there is limited research on the reproductive toxicity of SPAs, particularly in aquatic invertebrates. In this study, female Ruditapes philippinarum were selected as research objects to investigate the reproductive toxicity effects of typical SPAs 2,6-di-tert-butyl hydroxytoluene (BHT) on clams at different reproductive stages. The results showed that BHT downregulated the level of ovarian steroid hormones by disrupting steroid production, and showed anti-estrogenic effects. This interference impedes meiosis, follicular development, and ovulation, resulting in a decrease in the number of mature oocytes and gonadal index. Furthermore, exposure to BHT increased ROS levels and suppressed antioxidant defenses, resulting in biomacromolecular damage. BHT also induced apoptosis, ferroptosis, and pyroptosis in ovarian cells, impairing ovarian development. Collectively, this study elucidates the potential molecular mechanisms of reproductive toxicity caused by BHT in bivalve shellfish, focusing on endocrine disruption, oxidative damage, and cell death pathways. The findings provide data supporting the conservation of marine shellfish germplasm.

We reported 10 new copper(II) complexes 1-10 with pyrazolopyrimidine derivatives as ligands. Complexes 2 and 4 reacted with glutathione (GSH) in cells through Fenton-like reaction to generate highly toxic hydroxyl radical (·OH) for chemodynamic therapy (CDT), and reduced endogenous glutathione peroxidase 4 (GPX4) to induce ferroptosis. In addition, these complexes effectively caused mitochondrial dysfunction and induced apoptosis and autophagy in tumor cells. Furthermore, 2 and 4 effectively inhibited the bladder cancer cell growth in a xenograft model. This study presents new copper(II) complexes that can significantly induce bladder cancer cells death by enhanced CDT through bimodal apoptosis and ferroptosis, providing a promising approach for cancer therapy.

Necroptosis, a distinct form of regulated necrosis implicated in various human pathologies, is orchestrated through sophisticated signaling pathways. During this process, cells undergoing necroptosis exhibit characteristic necrotic morphology and provoke substantial inflammatory responses. Post-translational modifications (PTMs)-chemical alterations occurring after protein synthesis that critically regulate protein functionality-constitute essential regulatory components within these complex signaling cascades. This intricate crosstalk between necroptotic pathways and PTM networks presents promising therapeutic opportunities. Our comprehensive review systematically analyzes the molecular mechanisms underlying necroptosis, with particular emphasis on the regulatory roles of PTMs in signal transduction. Through systematic evaluation of key modifications including ubiquitination, phosphorylation, glycosylation, methylation, acetylation, disulfide bond formation, caspase cleavage, nitrosylation, and SUMOylation, we examine potential therapeutic applications targeting necroptosis in disease pathogenesis. Furthermore, we synthesize current pharmacological strategies for manipulating PTM-regulated necroptosis, offering novel perspectives on clinical target development and therapeutic intervention.

Ischemia-reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.

Spinal cord injury (SCI) is a devastating event for the central nervous system (CNS), often resulting in the loss of sensory and motor functions. It profoundly affects both the physiological and psychological well-being of patients, reducing their quality of life while also imposing significant economic pressure on families and the healthcare system. Due to the complex pathophysiology of SCI, effective treatments for promoting recovery remain scarce. Mesenchymal stem cell-derived exosomes (MSC-Exos) offer advantages such as low immunogenicity, good biocompatibility, and the ability to cross the blood-spinal cord barrier (BSCB). In preclinical studies, they have progressively shown efficacy in promoting SCI repair and functional recovery. However, the low yield and insufficient targeting of MSC-Exos limit their therapeutic efficacy. Currently, genetic engineering and other preprocessing techniques are being employed to optimize both the yield and functional properties of exosomes, thereby enhancing their therapeutic potential. Therefore, this paper provides an overview of the pathophysiology of SCI and the biogenesis of exosomes. It also summarizes current approaches to optimizing exosome performance. Additionally, it details the mechanisms through which optimized exosomes provide neuroprotection and explores the potential of combined treatments involving MSC-Exos and hydrogels.

Microcystin-LR (MC-LR), a class of cyclic heptapeptide compounds synthesized by cyanobacterial species, presents a significant risk to ecological systems and public health. Exposure to MC-LR was found to induce damage to various organs. One of the target organ systems affected by MC-LR is the gastrointestinal tract (GIT). However, the majority of studies regarding GIT focused on colorectal toxicity, with little attention paid to small intestinal toxic injuries, in particular jejunum. Thus, the aim of this study was to investigate the effects attributed to MC-LR exposure on apoptosis and underlying mechanisms utilizing a mouse jejunum injury model following chronic low-dose MC-LR treatment. A total of 40 C57BL/6 male mice were randomly divided into 4 groups with each group receiving drinking water containing 0, 1, 60, or 120 µg/L MC-LR for a duration of 12 months. Results indicated that exposure to MC-LR induced pathological alterations in jejunal tissue as evidenced by abnormal villous serration, crypt disorganization, and lymphocyte infiltration. TUNEL assays demonstrated a significant increase in apoptotic cell count in the 60 and 120 µg/L groups. The 60 and 120 µg/L MC-LR treatment groups exhibited elevated mRNA expression of Bax accompanied by significant reduction in mRNA expression of Bcl-2. The protein levels of cleaved caspase-3 were markedly elevated in the 60 and 120 µg/L MC-LR groups. The protein expression levels of p-RAF and p-ERK were significantly increased in the 60 and 120 µg/L MC-LR treatment groups. Data demonstrated suggest that the RAF/ERK signaling pathway may be involved in MC-LR- induced jejunal apoptosis.

Background : Multiple cell death modalities are implicated in sepsis pathobiology. However, the clinical relevance of NINJ1, a key mediator of plasma membrane rupture during lytic cell death, in sepsis progression and outcomes has remained poorly explored. Methods: Circulating NINJ1 levels were measured in 116 septic intensive care unit (ICU) patients, 16 nonseptic ICU controls, and 16 healthy controls. Comparative analysis of serum NINJ1 across these groups was performed. Correlations between NINJ1 and clinical disease severity scores (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation [APACHE II]) as well as laboratory parameters were examined in the sepsis cohort. Furthermore, we assessed the prognostic performance of NINJ1 for predicting 28-day mortality in septic patients using receiver operating characteristic (ROC) analyses. Results: Circulating NINJ1 levels were elevated in septic patients and positively correlated with sepsis severity scores. NINJ1 also showed positive correlations with liver injury markers (aspartate transaminase/alanine aminotransferase) and coagulation parameters (D-dimer, activated partial thromboplastin time, prothrombin time, thrombin time) in sepsis. Further analysis using the International Society on Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring system revealed an association between NINJ1 and sepsis-induced coagulopathy. ROC analysis demonstrated that NINJ1 outperformed traditional inflammatory biomarkers procalcitonin and C-reactive protein in predicting 28-day sepsis mortality, although its prognostic accuracy was lower than SOFA and APACHE II scores. Combining NINJ1 with SOFA improved mortality prediction from an area under the curve of 0.6843 to 0.773. Conclusions: Circulating NINJ1 serves as a novel sepsis biomarker indicative of disease severity, coagulopathy and mortality risk, and its integration with SOFA and APACHE II scores substantially enhances prognostic risk stratification. These findings highlight the prospective clinical utility of NINJ1 for sepsis prognostication and monitoring, warranting further validation studies to facilitate implementation.

Metazoans have evolved innate antimicrobial defenses that promote cellular survival and proliferation. Countering the inevitable molecular mechanisms by which microbes sabotage these pathways, multicellular organisms rely on an alternative, perhaps more ancient, strategy that is the immune equivalent of suicide bombing: Infection triggers cell death programs that summon localized or even systemic inflammation. The study of human genetics has now unveiled a level of complexity that refutes the naive view that cell death is merely a blunt instrument or an evolutionary afterthought. To the contrary, findings from patients with rare diseases teach us that cell death-induced inflammation is a sophisticated, tightly choreographed process. We herein review the emerging body of evidence describing a group of illnesses-inborn errors of cell death, which define many of the molecular building blocks and regulatory elements controlling cell death-induced inflammation in humans-and provide a possible road map to countering this process across the spectrum of rare and common illnesses.

Necroptosis is a finely regulated programmed cell death process involving complex molecular mechanisms and signal transduction networks. Among them, receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein are the key molecules regulating this process. In recent years, gasotransmitters such as nitric oxide, carbon monoxide and hydrogen sulfide have been suggested to play a regulatory role in necroptosis. This paper reviews the evidence that these gasotransmitters are involved in the regulation of necroptosis by influencing the production of reactive oxygen species, regulating the modification of S subunits of RIPK1 and RIPK3, regulating inflammatory mediators, and signal transduction. In addition, this review explores the potential therapeutic applications of these gasotransmitters in pathological conditions such as cardiovascular disease and ischemia-reperfusion injury. Although some studies have revealed the important role of gasotransmitters in necroptosis, the specific mechanism of action is still not fully understood. Future research is needed to further elucidate the molecular mechanisms of gasotransmitters in precisely regulating necroptosis, which will help develop new therapeutic strategies to prevent and treat related diseases.

SNS-032 is a synthetic compound that specifically inhibits cyclin-dependent kinases 2, 7 and 9. Its primary anticancer activity involves cell cycle arrest, which prevents tumor cell growth. However, there are limited reports on whether SNS-032 induces pyroptosis, a novel inflammation-mediated programmed cell death pathway in breast cancer (BC). The present study demonstrated that SNS-032 treatment decreased cell viability by inducing pyroptosis in BC cells. Typical morphological indications of pyroptosis were observed, including cell swelling and destruction of cell membrane integrity, leading the release of adenosine 5'-triphosphate and lactate dehydrogenase. Furthermore, the expression of caspase-3, the N terminus of gasdermin E (GSDME) and B-cell lymphoma-2 (BCL-2)-associated X protein increased, whereas expression of BCL-2 decreased. In addition, Z-DEVD-FMK, a specific caspase-3 inhibitor, markedly alleviated pyroptosis triggered by SNS-032. These findings suggested that SNS-032 induced caspase-3/GSDME-dependent pyroptosis. Furthermore, the present study demonstrated that decitabine (DAC), a DNA methyltransferase inhibitor, upregulated the expression of GSDME protein and enhanced SNS-032-induced caspase-3/GSDME-dependent pyroptosis in BC cells. In conclusion, these results suggest that caspase-3/GSDME-induced pyroptosis can be facilitated by SNS-032 treatment in BC cells, and DAC has the potential to enhance SNS-032-induced pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS-032 is a promising therapeutic agent for BC treatment.

Hepatic steatosis significantly elevates the vulnerability of the graft to ischemia-reperfusion (I/R) injury during liver transplantation (LT). We investigated the protective role of insulin-induced gene 2 (Insig2) in steatotic liver's I/R injury and underlying mechanisms. Employing mouse model with Insig2 knock-out or hepatocyte-specific overexpression and high-fat diets to induce steatosis, we subjected these mice to hepatic I/R injury. The primary hepatocytes isolated from steatotic liver were used in in vitro hypoxia/reoxygenation (H/R) experiment. Our integrated in vivo and in vitro approach uncovered that Insig2 deficiency exacerbated steatotic liver's damage following hepatic I/R injury, whereas its overexpression offers protection. Mechanically, integrative analysis of transcriptome, proteome, and metabolome found that Insig2 deficiency disturbed lipid metabolism and oxidative stress homeostasis, particularly inhibiting GPX4 expression to induce ferroptosis. Furthermore, chemical inhibition of ferroptosis reversed the deleterious effect of Insig2 deficiency; whereas the protective influence of Insig2 overexpression was negated by the target inhibition of GPX4, leading to an exacerbation of hepatic I/R damage. These insights underscored the potential of the Insig2-GPX4 axis as a therapeutic target, presenting a novel avenue for enhancing the resilience of steatotic liver grafts against I/R injury.

Necroptosis plays a crucial role in the progression of various diseases and has gained substantial attention for its potential to activate antitumor immunity. However, the complex signaling networks that regulate necroptosis have made it challenging to fully understand its mechanisms and translate this knowledge into therapeutic applications. To address these challenges, an optogenetically activatable necroptosis system is developed that allows for precise spatiotemporal control of key necroptosis regulators, bypassing complex upstream signaling processes. The system, specifically featuring optoMLKL, demonstrates that it can rapidly assemble into functional higher-order "hotspots" within cellular membrane compartments, independent of RIPK3-mediated phosphorylation. Moreover, the functional module of optoMLKL significantly enhances innate immune responses by promoting the release of iDAMPs and cDAMPs, which are critical for initiating antitumor immunity. Furthermore, optoMLKL exhibits antitumor effects when activated in patient-derived pancreatic cancer organoids, highlighting its potential for clinical application. These findings will pave the way for innovative cancer therapies by leveraging optogenetic approaches to precisely control and enhance necroptosis.

Necroptosis is a programmed cell death form executed by receptor-interacting protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain-like protein (MLKL), which assemble into an oligomer called necrosome. Accumulating evidence reveals that necroptosis participates in many types of pathological processes. Hence, clarifying the mechanism of necroptosis in pathological processes is particularly important for the prevention and treatment of various diseases. For over 300 years, hydrogen sulfide (H2S) has been widely known in the scientific community as a toxic and foul-smelling gas. However, after discovering the important physiological and pathological functions of H2S, human understanding of this small molecule changed, believing that H2S is the third gas signaling molecule after carbon monoxide (CO) and nitric oxide (NO). H2S plays an important role in various diseases, but the related mechanisms are not yet fully understood. In recent years, more and more studies have shown that H2S regulation of necroptosis is involved in various pathological processes. Herein, we focus on the recent progress on the role of H2S regulation of necroptosis in different pathological processes and profoundly analyze the related mechanisms.

As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction in neuronal loss, glial activation, and neuroinflammation. OTUB2 was predominantly expressed in neurons and its deletion decreased receptor-interacting protein kinase 3 (RIPK3)-mediated neuronal necroptosis. Moreover, OTUB2 increased RIPK3 protein abundance by inhibiting the proteasomal degradation of RIPK3. Mechanistically, OTUB2 removed K48-linked polyubiquitin chains from RIPK3 through its active site C51. Importantly, pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and reduced oxygen-glucose deprivation-induced neuronal death in human brain organoids. These results demonstrate that OTUB2 critically regulates ischemic stroke injury by potentiating neuronal necroptosis, suggesting that OTUB2 inhibition may become a potential therapeutic approach for treating ischemic stroke.

Sorafenib, a multi-target tyrosine kinase inhibitor, is primarily used to manage hepatocellular carcinoma, advanced renal cell carcinoma, and differentiated thyroid cancer. Although this drug extends patient survival and slows tumor progression, its cardiovascular toxicity substantially impacts of quality of life. Effective the prevention and treatment of the resulting complications are needed. The mechanisms underlying of sorafenib-induced cardiovascular toxicity are complex, and remain incompletely understood despite extensive research. In this review, we discuss the incidence of sorafenib-induced cardiovascular toxicity, including hypertension, thromboembolism, and heart failure in clinical settings. We also summarize current research on the underlying mechanisms, such as ferroptosis, necroptosis, autophagy, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we explore studies regarding the protective effects of various drugs against sorafenib-induced cardiovascular toxicity. This in-depth synthesis of data regarding the clinical manifestations and mechanisms of sorafenib-induced cardiotoxicity provides a valuable scientific foundation for developing therapeutic drugs to combat these adverse effects.

Cervical cancer (CC) patients have a poor prognosis and a low 1-year survival rate due to recurrence or pelvic metastasis. The GSE9750 dataset was analyzed to identify hub genes in CC. CCK-8, colony formation assay, EdU, TUNEL, Transwell assays, and western blot analysis for apoptosis-associated markers were conducted to examine CC cell malignant phenotype after different lentiviral vector treatments. Dual-luciferase assay, ChIP, and MSP were used for regulatory assays. P53-regulated apoptosis-inducing protein 1 (TP53AIP1) was lowly expressed in CC tissues and cell lines, and TP53AIP1 overexpression repressed proliferation, migration, and invasion, and induced apoptosis of CC cells by activating the p53 signaling. DNMT3A bound to the TP53AIP1 promoter and transcriptionally repressed TP53AIP1 expression. DNA-methyltransferase 3A (DNMT3A) silencing inhibited CC development and lung metastasis in vivo, but further TP53AIP1 knockdown reversed this phenomenon by disrupting p53-mediated apoptosis. In summary, DNMT3A transcriptionally repressed TP53AIP1 expression to promote CC progression and metastasis.

There has been abundant research on the variety of programmed cell death pathways. Apoptosis, pyroptosis, and necroptosis under the action of the caspase family are essential for the innate immune response. Caspases are classified into inflammatory caspase-1/4/5/11, apoptotic caspase-3/6/7, and caspase-2/8/9/10. Although necroptosis is not caspase-dependent to transmit cell death signals, it can cross-link with pyroptosis and apoptosis signals under the regulation of caspase-8. An increasing number of studies have reiterated the involvement of the caspase family in acute lung injuries caused by bacterial and viral infections, blood transfusion, and ventilation, which is influenced by noxious stimuli that activate or inhibit caspase engagement pathways, leading to subsequent lung injury. This article reviews the role of caspases implicated in diverse programmed cell death mechanisms in acute lung injury and the status of research on relevant inhibitors against essential target proteins of the described cell death mechanisms. The findings of this review may help in delineating novel therapeutic targets for acute lung injury.

Gasdermin D (GSDMD) has garnered significant attention primarily for the pore-forming role of its p30 N-terminal fragment (NT-p30) generated during pyroptosis, a proinflammatory form of cell death. However, emerging evidence suggests that the formation of GSDMD-NT pores is reversible, and the activation of GSDMD does not necessarily lead to pyroptosis. Instead, this process may take part either in other forms of cell death, or in various state changes of living cells, including (i) inflammation regulation, (ii) endolysosomal pathway rewiring, (iii) granule exocytosis, (iv) type II immunity, (v) food tolerance maintenance, and (vi) temporary permeability alteration. This review explores the latest insights into the involvement of GSDMD in cell death and homeostasis maintenance, aiming to underscore the pleiotropic nature of GSDMD.