Myocardial ischemia-reperfusion (I/R) injury remains a major challenge in cardiovascular interventions. Although conventional reperfusion therapies restore coronary blood flow, they can often exacerbate myocardial damage. In recent years, ferroptosis, a novel form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal contributor to myocardial I/R injury. Unlike apoptosis and necrosis, ferroptosis is driven by the accumulation of reactive iron and the peroxidation of membrane phospholipids enriched with polyunsaturated fatty acids (PUFAs), processes that are tightly regulated by lipid metabolism. However, the precise mechanisms linking lipid metabolic reprogramming to ferroptosis during myocardial I/R injury remain incompletely understood. To address this gap, this review systematically examines the interplay between lipid metabolism and ferroptosis in myocardial I/R injury. We highlight the roles of fatty acid uptake, β-oxidation, phospholipid remodeling, cholesterol metabolism, and mitochondria-lipid droplet interactions in forming a deleterious cycle of metabolic disruption, oxidative stress, and membrane damage. Key regulators, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and cluster of differentiation 36 (CD36), are emphasized for their roles in contributing to ferroptotic vulnerability. Moreover, the review also explores the protective roles of short-chain fatty acids (SCFAs) and 7-dehydrocholesterol (7-DHC) as emerging anti-ferroptotic agents. Novel yet understudied mechanisms with therapeutic potential are also discussed, including Rab8a-PLIN5-mediated lipid droplet trafficking and 7-DHC reductase (DHCR7) deficiency-induced 7-DHC accumulation. Collectively, this review provides a comprehensive framework for understanding the lipid metabolism-ferroptosis axis in myocardial I/R injury, offering insights for future mechanistic studies and clinical translation.

The acidic and inflammatory microenvironment serves as a central pathological feature of intervertebral disc degeneration (IVDD), acting as a critical driving factor in disease progression. However, the interplay between acidic and inflammatory microenvironments remains largely unexplored. In this study, we revealed the molecular mechanism by which crosstalk between glycolysis and pyroptosis exacerbates IVDD. We observed that lactic acid stimulation triggers pyroptosis in NPCs by stimulating the NLRP3 inflammasome, activating the caspase-1 pathway, and upregulating the expressions of IL-1β and IL-18. Acid sensitive ion channel 1a (ASIC1a) expression is positively correlated with extracellular acidosis severity and NPC pyroptosis levels. Furthermore, the knockdown of ASIC1a via siRNA effectively alleviated pyroptosis. After treatment of NPCs with IL-1β, glycolysis levels were increased, accompanied by up-regulation of c-Myc (a key regulator of the Warburg effect) and nuclear translocation, the knockdown of c-Myc effectively alleviated glycolysis. Mechanistically, lactate activates acid-sensing ion channel 1a (ASIC1a), which mediates Ca influx to promote pyroptosis in nucleus pulposus cells (NPCs) and IL-1β release. Secreted IL-1β subsequently induces the nuclear translocation of, thereby upregulating glycolytic enzyme expression, enhancing glycolysis, and accelerating lactate accumulation. This cascade establishes a vicious cycle that progressively aggravates IVDD. Our findings demonstrate that glycolysis‒pyroptosis crosstalk promotes acid‒inflammatory microenvironments in degenerated discs, driving disease progression. Targeted inhibition of this crosstalk improves disc biological function and mitigates IVDD progression.

Diabetic nephropathy is a prevalent complication of diabetes mellitus, characterized by progressive renal failure, a leading cause of end-stage renal disease. The pathogenesis of diabetic nephropathy is intricate, with recent research highlighting the significant roles of endoplasmic reticulum stress and ferroptosis in its development. Endoplasmic reticulum stress is initiated by the accumulation of misfolded proteins in the endoplasmic reticulum, activating the unfolded protein response. Ferroptosis, an iron-dependent form of programmed cell death, involves iron ion buildup and heightened lipid peroxidation. In diabetic nephropathy, persistent endoplasmic reticulum stress and ferroptosis intensify renal inflammation, fibrosis, and apoptosis, which are crucial processes in the development of the condition. This review seeks to clarify the molecular mechanisms and interactions between endoplasmic reticulum stress and ferroptosis in diabetic nephropathy, as well as anticipate innovative therapeutic strategies that target endoplasmic reticulum stress and ferroptosis to slow down disease advancement and provide hope for individuals affected by diabetic nephropathy.

Intestinal injury is a common and potentially life-threatening complication in patients receiving concurrent radiotherapy (RT) and anti-PD-1 immunotherapy (IO) for pelvic, abdominal, or retroperitoneal malignancies. Despite the therapeutic benefits of RT/IO combinations the mechanisms underlying RT/IO-induced enteritis remain poorly understood. This study investigates the role of Absent in melanoma 2 (AIM2)-mediated PANoptosis in intestinal barrier dysfunction during RT/IO-induced enteritis. Colonic epithelial cell models and murine models were utilized to assess the activation of PANoptosis pathways, barrier function, and inflammation. AIM2 expression was silenced using CRISPR-Cas9-mediated knockout. Western blotting and immunohistochemistry were employed to assess PANoptosis markers. Barrier function was evaluated using transepithelial electrical resistance (TEER) and FITC-dextran permeability assays. Quasi-targeted metabolomics identified metabolic alterations associated with intestinal injury. Combined RT and IO significantly exacerbated intestinal epithelial damage, as evidenced by increased PANoptosis and compromised barrier function both in vivo and in vitro. AIM2 expression was markedly upregulated following RT/IO treatment. RT/IO treatment activated the JAK3/STAT1 signaling pathway, and pretreatment with the JAK3 inhibitor AG490 inhibited AIM2 expression, while cellular AIM2 knockout attenuated PANoptosis markers, preserved tight junction protein ZO-1, and improved barrier function. Metabolomics analysis showed that RT/IO treatment significantly disturbed intestinal choline metabolism in mice, which may be related to the cell death pathway. Supplementation with choline or its metabolite trimethylamine N-oxide (TMAO), especially TMAO, upregulated JAK3/STAT1 and AIM2-PANoptosis pathways, and aggravated intestinal injury, whereas supplementation of mice with 3,3-Dimethyl-1-butanol (DMB) to reduce the production of TMAO reversed the activation of the choline-induced pathway and inflammatory response. AIM2-driven PANoptosis, activated by the JAK3/STAT1 pathway, plays a key role in RT/IO-induced intestinal damage. Elevated choline metabolism and TMAO accumulation further amplify this pathological process by enhancing JAK3/STAT1 and AIM2 activity. Inhibiting JAK3 or TMAO reduces PANoptosis, offering a potential preclinical treatment to alleviate RT/IO intestinal toxicity.

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein plays a central role in regulating mitochondrial metabolism, energy production, and apoptosis. VDAC1 interacts with over 100 proteins across the cytosol, endoplasmic reticulum, plasma membrane, and mitochondrial membranes. These interactions coordinate metabolism, cell death, and signal transduction, integrating mitochondrial and cellular functions. To identify VDAC1 binding sites, we designed a peptide array of 768 peptides from 19 selected VDAC1-interacting proteins. We focused on three partners: GAPDH, gelsolin, and actin. Their VDAC1-binding sequences as peptides interacted with purified VDAC1 and, as cell-penetrating peptides, induced cell death, and elevated intracellular Ca⁺ and ROS levels. Despite sequence diversity, the peptides converged on enhancing transcription factors p53 and c-Jun, upregulating VDAC1, promoting its oligomerization, and triggering apoptosis. Other effects related to their originated protein's function include no significant effect of the GAPDH-derived peptide on its catalytic activity, indicating its effects are independent of glycolysis. The gelsolin-derived peptide altered actin organization, increasing filopodia and focal adhesion, and actin-derived peptides reduced actin, gelsolin, and tubulin expression. This study is the first to identify VDAC1 binding sites on 19 interacting partners and to demonstrate their use as cell-penetrating peptides to modulate the VDAC1 network. These findings highlight VDAC1's multifaceted regulatory role and offer a novel approach for targeting VDAC1-protein interactions for therapeutic purposes.

Actin gamma 1 (ACTG1) encodes the cytoskeletal protein γ-actin and is overexpressed in various cancers. Cisplatin-based chemotherapy is the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, most patients eventually develop cisplatin resistance. The association between ACTG1 and cisplatin resistance remains unclear. In this study, we found that high expression of ACTG1 was associated with poor prognosis in NSCLC. Knockdown of ACTG1 promoted mitochondrial fragmentation via interaction with the fusion protein MFN2 and induced ferroptosis. Mechanistically, ACTG1 knockdown disrupted mitochondrial dynamics, elevated mitochondrial ROS, reduced glutathione (GSH) levels, and enhanced lipid peroxidation. This cascade significantly inhibited the growth of cisplatin-resistant NSCLC cells and sensitized them to cisplatin. Furthermore, the ferroptosis inducer RSL3 synergized with cisplatin to enhance ferroptosis and mitochondrial fragmentation, effectively sensitizing ACTG1-overexpressing cells both in vitro and in xenograft models. Our findings establish ACTG1 as a critical mediator of cisplatin resistance in NSCLC through regulation of mitochondrial integrity and ferroptosis. Targeting the ACTG1-MFN2 axis combined with ferroptosis induction represents a promising therapeutic strategy to overcome cisplatin resistance.

Neutrophil-mediated inflammation plays a crucial role in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Dysregulated neutrophil death has been implicated in promoting neutrophil priming and activation. PANoptosis, an inflammatory programmed cell death, participates in the development of various autoimmune diseases. The current study aims to identify the key PANoptosis-related marker and investigate its association with disease activity of AAV. Gene microarray data of patients with ANCA-associated glomerulonephritis (ANCA-GN) was downloaded from the Gene Expression Omnibus (GEO). PANoptosis-associated genes were sourced from GeneCards. The hub-marker of PANoptosis-related genes was identified by integrated bioinformatical analysis. The single-cell sequencing data from ANCA-GN mice were used to determine the location of hub genes. Then levels of activated CD11b on neutrophils from peripheral blood, as well as soluble CD11b in urine and plasma were measured in AAV patients. Their associations with clinicopathological parameters of AAV patients were subsequently analyzed. Co-localization of CD11b and neutrophils in renal specimens of AAV patients was evaluated by immunofluorescence staining. Changes of intracellular metabolic pathways of neutrophils from AAV patients were further investigated. A small molecule inhibitor was used to explore the effect of intracellular fatty acid metabolism (FAO) on neutrophil CD11b activation and PANoptosis. CD11B was identified as the pivotal PANoptosis-related gene in AAV by integrated bioinformatics analysis. The level of activated CD11b on neutrophils was significantly higher in active AAV patients compared with healthy controls, and elevated neutrophil CD11b levels positively correlated with disease activity, as evidenced by higher levels of hypersensitive C-reactive protein (hCRP), increased Birmingham Vasculitis Activity Score (BVAS), elevated serum creatinine levels at sampling and a higher proportion of cellular crescents in renal specimens of AAV patients. We also demonstrated the presence of neutrophil CD11b in renal specimen of AAV patients. Moreover, along with elevated Cd11b expression, neutrophils from ANCA-GN mice exhibited an aberrant FAO phenotype and a down-regulated peroxisome proliferators-activated receptor (PPAR)-α pathway, as compared with healthy controls. GW7647, a PPARα agonist, could alleviate AAV serum-induced neutrophil CD11b activation and PANoptosis. CD11B was a pivotal PANoptosis-related gene in AAV. The level of activated CD11b on neutrophils was associated with disease activity in AAV patients.

Adipose-derived stem cells (ASCs) can shift toward proinflammatory and fibrotic phenotypes, but factors triggering this transition are not fully understood. This study aimed to elucidate the impact of exposure to regulated cell death environments on the fibroinflammatory potential of surviving subcutaneous ASCs (sub-ASCs). Surviving sub-ASCs were characterized by transcriptional analysis of genes associated with inflammation and extracellular matrix remodeling. Phenotypical markers of fibroinflammatory progenitor cells were monitored by immunoblotting and flow cytometry. We determined post-translational modifications (PTMs) of histone proteins by immunoblotting and mass spectrometry, including individual and combinatorial histone marks. Four days after transient exposure to serum starvation- or tumor necrosis factor-alpha (TNFα)-induced cell death, surviving sub-ASCs cultured under hypoxic proliferative conditions showed elevated mRNA levels of inflammatory mediators, fibrillar collagens, matricellular proteins, and cytoskeletal components. This fibroinflammatory transcriptional activation was accompanied by decreased expression of fibroinflammatory progenitor cell markers. Surviving sub-ASCs exhibited variations in histone methylation marks associated with transcriptional regulation. Inhibiting calcium-dependent μ- and m-calpains during TNFα-induced cell death increased histone marks associated with gene activation and repression, altering surviving sub-ASCs transcriptional responses four days later. Middle-down mass spectrometry identified changes in specific histone mark combinations in surviving sub-ASCs following TNFα-induced cell death. These findings suggest that regulated cell death environments act as reprogramming agents for surviving ASCs, driving fibro-inflammatory transcriptional activation and histone PTM changes, likely as part of an inducible gene expression program promoting cell survival.

Astragaloside IV (AS-IV), a bioactive compound renowned for its anti-inflammatory, antioxidant, and anti-apoptotic properties, has not yet been investigated for its potential role in modulating cardiac function under high-altitude conditions. This study elucidates the cardioprotective effects of AS-IV against high-altitude-induced cardiac injury and explores the underlying molecular mechanisms. Under hypobaric hypoxia, we observed significant cardiac dysfunction, hypertrophy, and fibrosis, as confirmed by comprehensive echocardiographic, histopathological, and molecular analyses. Remarkably, AS-IV administration effectively attenuated these pathological changes, restoring cardiac architecture and function while mitigating oxidative stress and apoptosis. Further in vivo and in vitro experiments revealed that AS-IV preserves mitochondrial integrity by enhancing membrane potential, ameliorating mitochondrial impairment, and modulating calcium homeostasis through the calcium-sensing receptor (CaSR)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis. Network pharmacology-based screening identified key molecular targets, including epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mouse double minute 2 (MDM2), which were subsequently validated via molecular docking studies demonstrating strong binding affinities between AS-IV and these core proteins. Mechanistic investigations further revealed that siRNA-mediated EGFR knockdown or pharmacological activation of CaSR abolished AS-IV's cardioprotective effects, including its anti-apoptotic, antioxidant, and mitochondrial-stabilizing properties. Taken together, our findings demonstrate that AS-IV exerts its therapeutic effects through a dual-pathway mechanism involving (1) the EGFR-PI3K-AKT-MDM2 axis and (2) CaSR-NF-κB signaling. These insights position AS-IV as a promising candidate for the prevention and treatment of high-altitude-related cardiovascular diseases.

Sepsis, a life-threatening condition, involves dysregulated cholesterol metabolism critical for immune regulation and cellular processes. This study employed multi-omics and machine learning to explore cholesterol metabolism in sepsis, aiming to identify novel therapeutic targets. Transcriptome and single-cell RNA sequencing data for sepsis were retrieved from the Gene Expression Omnibus (GEO) database. The limma package and WGCNA co-expression network were used to screen genes, hybridized with cholesterol metabolism genes (CMGs) to identify hub genes. Machine learning algorithms screened pivotal genes to construct diagnostic model, validating performance via multi-cohort Receiver Operating Characteristic (ROC) curve. Non-negative matrix factorization (NMF) based molecular typing using CMGs, and integration of 101 machine learning algorithms built prognostic models. Single-cell analysis characterized expression patterns of pivotal genes and key subsets. Causal effects and phenotypic associations of target genes were evaluated using Summary data-based Mendelian Randomization (SMR) and PheWAS. Integrated transcriptomic analysis identified three key genes (VDAC1, VDAC2, and LDLRAP1) associated with dysregulated cholesterol metabolism in sepsis. Machine learning-based diagnostic models exhibited high predictive accuracy. NMF clustering revealed two molecular subtypes, with Cluster 1 characterized by immunosuppression and metabolic reprogramming, linked to poorer prognosis. A machine learning model integrating 101 algorithms predicted 28-day mortality. The single-cell transcriptome atlas identified CD14CD163 monocytes as the hub cell population in the immune microenvironment of sepsis, and the active cholesterol metabolic pathway might constitute the core for regulating the immune response. Elevated VDAC2 expression was significantly correlated with reduced sepsis risk, as determined by SMR analysis. This study underscored cholesterol metabolism's critical role in sepsis pathogenesis. Multi-omics nominates VDAC2 as a candidate protective locus in sepsis-associated cholesterol dysregulation.

Lactate, the primary byproduct of glycolysis, has been established as a critical barometer of tumor microenvironment homeostasis and is implicated in tumor progression. Alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) have been identified as sensors of intracellular L-lactate and as contributors to cancer development. Nonetheless, investigations into the different roles of AARS1 and AARS2 across various cancer types remain lacking. In this study, we preliminarily explored the correlations between AARS1/2 and the tumor microenvironment in pan-cancer. We first examined the expression patterns of AARS1 and AARS2 across 33 cancer types. Subsequently, we analyzed the relationship of AARS1/2 with clinical features and mutational landscape utilizing the GSCA and cBioPortal databases. Survival outcomes associated with AARS1/2 were assessed through Cox regression and the Kaplan-Meier method. Additionally, we examined the correlations between AARS1/2 and drug sensitivity, as well as immune infiltration, using the GSCA database, TISIDB database, and the CIBERSORT algorithm, respectively. Notably, significant heterogeneity of AARS1 and AARS2 was observed across various dimensions, including expression profiles, clinical outcomes, mutation spectra, and immune infiltration. The expression patterns of AARS1/2 were statistically different in urologic neoplasms. Similarly, survival analysis revealed a close correlation between elevated AARS1 expression and unfavorable prognosis in patients with urologic neoplasms, while AARS2 expression level was not. Interestingly, the results of immune infiltration indicated the statistical heterogeneity of AARS1 and AARS2 in certain urologic neoplasms, especially in bladder urothelial carcinoma (BLCA). Specifically, (1) the correlation between AARS1/2 expression and immune-related scores in BLCA was opposite; and (2) TIDE analysis demonstrated that elevated AARS1 expression was related to a high TIDE score in BLCA, while AARS2 was not. Further detailed analysis of AARS1 and AARS2 in the context of immune infiltration and functional enrichment in BLCA may partially account for these observations. In conclusion, our findings highlighted the heterogeneity of AARS1 and AARS2 across various cancers. Based on our data, AARS1 was identified as a potential prognostic biomarker and a candidate for immunotherapy targeting in urologic cancers, though further validation is needed to confirm its clinical utility.

Sodium butyrate (NaB), a major intestinal metabolite, has been suggested to protect against osteoporosis (OP). This study aimed to elucidate the mechanism by which NaB regulates ferroptosis in OP. An ovariectomy-induced mouse OP model was established, and treated with NaB or the ferroptosis inhibitor Fer-1. Bone mineral density, bone microstructure, bone formation and resorption, and ferroptosis markers were assessed. In vitro, mouse bone marrow mesenchymal stem cells (BMSCs) were treated with NaB and the ferroptosis inducer Erastin to evaluate osteogenic differentiation and ferroptosis. Phosphatase and tensin homolog (PTEN) acetylation was detected by co-immunoprecipitation, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was evaluated by Western blot, and acetylation sites by point mutation. The role of PTEN acetylation was further validated using the p300 inhibitor C646 in vitro and in vivo. NaB treatment enhanced bone formation, suppressed ferroptosis, and promoted osteogenic differentiation in OP mice, mimicking the protective effects of Fer-1. In BMSCs, NaB promoted osteogenesis by inhibiting ferroptosis. Mechanistically, NaB induced acetylation of PTEN at K125/K128, suppressing its phosphatase activity and activating the PI3K/AKT pathway, thereby reducing ferroptosis. C646 partially abolished these effects. NaB promotes PTEN acetylation at K125/K128 to activate PI3K/AKT signaling, thereby inhibiting ferroptosis and alleviating estrogen deficiency-induced OP. These findings highlight NaB as a potential epigenetic metabolic regulator of bone metabolism.

Renal ischemia-reperfusion injury (IRI) remains a critical obstacle to optimal renal transplant outcomes, driving acute graft dysfunction and long-term allograft failure. While ferroptosis-an iron-dependent form of cell death-has been linked to IRI pathogenesis, the role of lipocalin-2 (LCN2), a regulator of iron homeostasis and inflammation, in transplant-related renal IRI remains uncharacterized. Six murine IRI transcriptomic datasets (83 samples) were integrated using weighted gene co-expression network analysis (WGCNA) and differential expression profiling to screen for IRI-associated hub genes. Findings were validated in two human transplant cohorts (212 samples) via 113 machine learning algorithms, including logistic regression, random forest, and ensemble models. Single-cell RNA sequencing (GSE237429) was used to map gene expression to specific renal cell populations, while a murine warm IRI model evaluated the effects of LCN2 inhibition (ZINC00640089) on tubular injury, ferroptosis markers (MDA, GSH, Fe²⁺), and inflammatory cytokines (IL-6, TNF-α) across mild (50-minute) and severe (80-minute) ischemia subgroups. WGCNA identified 36 hub genes, with LCN2 emerging as a key node in ferroptosis and immune regulation pathways. A six-gene machine learning model, including LCN2, CLU, and SOX9, demonstrated robust predictive accuracy for IRI (AUC = 0.93). Single-cell analysis revealed elevated LCN2 expression in neutrophils and macrophages in IRI kidneys, correlated with increased immune cell infiltration. In vivo, LCN2 inhibition significantly reduced severe ischemia-induced tubular injury, suppressed lipid peroxidation (MDA), restored glutathione levels (GSH), and alleviated iron overload (Fe) and reactive oxygen species (ROS). Systemic inflammation was mitigated, with IL-6 and TNF-α levels significantly reduced. This study establishes LCN2 as a pivotal mediator of ferroptosis and immune dysregulation in transplant IRI. A machine learning-driven multi-omics approach provides a novel diagnostic framework, while the inhibition of LCN2 is shown to alleviate IRI-induced tissue damage in these models. These findings highlight the utility of integrative analytics in uncovering biological targets and offer new therapeutic avenues for improving kidney transplant outcomes.

PANoptosis, a newly defined, multifaceted programmed cell death (PCD) pathway, integrates key features of pyroptosis, apoptosis, and necroptosis. It is orchestrated by multiprotein complexes called PANoptosomes (ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes), which assemble via domain interactions in response to specific pathogen- or damage-associated signals. This integrated pathway plays crucial roles in maintaining tissue homeostasis by eliminating infected and damaged cells and provides potent innate immune defence through the coordinated release of inflammatory cytokines and damage-associated molecular patterns (DAMPs), offering superior pathogen clearance compared with single PCD modes. Increasing evidence underscores the significant involvement of PANoptosis in digestive diseases. In gastric cancer, it modulates tumour progression, the immune microenvironment and chemoresistance. PANoptosis drives epithelial cell death in ulcerative colitis and Crohn's disease, contributing to mucosal barrier disruption and inflammation. It influences immune infiltration, metabolic reprogramming, and therapeutic response in colorectal cancer. PANoptosis also contributes to the pathogenesis of diverse liver conditions, including failure, fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma, and mediates pancreatic injury in acute pancreatitis. While research on oesophageal and pancreatic malignancies is nascent, PANoptosis-based molecular subtyping and therapeutic targeting demonstrate translational potential. This review synthesizes current evidence, highlighting PANoptosis as a critical regulator in digestive pathologies and as a promising target for intervention.

Beyond its established role as a lysine acetyltransferase, KAT2A has recently been identified to possess succinyltransferase activity. This study aims to investigate the function of KAT2A in mediating succinylation modification of heat shock protein 60 (HSP60) and to elucidate the underlying mechanism through which KAT2A regulates mitochondrial oxidative stress and ferroptosis induced by glucose starvation in colon cancer cells via HSP60 succinylation. Bioinformatic analyses were conducted to assess KAT2A expression in colon cancer and its association with patient prognosis. Protein interaction between KAT2A and HSP60 was examined by co-immunoprecipitation (Co-IP). Intracellular Fe²⁺ levels, lipid peroxidation, and mitochondrial reactive oxygen species (mtROS) were measured using FerroOrange, C11 BODIPY 581/591, and MitoSOX Red fluorescent probes, respectively. Mitochondrial localization and membrane potential were evaluated via immunofluorescence assays. KAT2A is upregulated in colon cancer and correlates with poor prognosis, largely attributable to its ability to enhance cell viability and invasion under glucose deprivation. Overexpression of KAT2A conferred resistance to glucose starvation-induced ferroptosis by mediating HSP60 succinylation. Label-free quantitative proteomic analysis identified three critical succinylation sites on HSP60 (K72, K133, K191), with K191 being the principal site regulating ferroptosis. Succinylated HSP60 interacts with GSTK1 and promotes the mitochondrial translocation of the HSP60-GSTK1 complex, mitigating mitochondrial oxidative stress under glucose starvation. Through this mechanism, KAT2A suppresses ferroptosis and supports colon cancer cell survival and tumor growth. The KAT2A-HSP60-GSTK1 axis attenuates glucose starvation-induced mitochondrial oxidative stress, thereby inhibiting ferroptosis and promoting tumor progression in colon cancer.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Tumor epithelial cells play a crucial role in shaping the tumor microenvironment (TME) and driving cancer progression. This study utilized a multi-omics approach, integrating data from 21 multi-center CRC cohorts (n = 2,767), including single-cell transcriptomics, bulk transcriptomics, spatial transcriptomics, and proteomics. Bioinformatic analyses were combined with in vitro and in vivo experiments for validation. A distinct epithelial subpopulation, ERO1A-positive epithelial cells (ERO1A + Epi), was identified and found to be significantly enriched in advanced-stage CRC, correlating with poor prognosis. ERO1A + Epi cells promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, while in vivo models confirmed their role in tumor growth and liver metastasis. Spatial and intercellular interaction analyses revealed that ERO1A + Epi cells interact with CTHRC1 + cancer-associated fibroblasts (CTHRC1 + CAFs) and SPP1 + macrophages via MDK-LRP1, MIF-(CD74 + CD44), and APP-CD74 signaling pathways, fostering a pro-tumorigenic TME. Co-culture experiments demonstrated that ERO1A + Epi enhances the expression of CTHRC1 and SPP1. A risk prediction model (ETSRM) based on the ERO1A + Epi_TME_Score demonstrated superior prognostic accuracy over 111 existing CRC models. Integrating ETSRM with TNM staging further enhanced survival prediction. Our findings identify ERO1A + Epi as a significant driver of colorectal cancer progression. The ERO1A + Epi_TME_Score-based ETSRM provides a robust prognostic tool, offering new insights into CRC pathogenesis and highlighting potential therapeutic targets for improved patient outcomes.

Immune checkpoint inhibitors (ICIs) have shown promise in enhancing non-small cell lung cancer (NSCLC) patient prognoses, but their effectiveness is contingent upon the specific tumor microenvironment (TME). In this research, we examined the heterogeneity and plasticity of tumor-associated macrophages in lung adenocarcinoma (LUAD) using single-cell sequencing data GSE207422, identifying genes that may influence their polarization. We identified a positive correlation between BCAT1 expression in immune-resistant patient tissues and M2 macrophage infiltration. Pseudo-temporal analysis revealed a significant overlap between BCAT1 expression dynamics and the trajectory of macrophage M2 polarization. Evidence from both in vitro and in vivo studies indicated that BCAT1 might foster an immunosuppressive environment by driving M2 macrophage polarization, which could account for the aggressive spread of LUAD and suboptimal responses to immunotherapy. Overall, our findings flagged BCAT1-high-expressing macrophages as a suppressive element in the TME, hinting that targeting BCAT1 could shift macrophage polarization and enhance patient outcomes.

PANoptosis is an inflammatory programmed cell death pathway. It integrates apoptosis, pyroptosis, and necroptosis via PANoptosome complexes, thereby coordinating immune responses and remodeling tumor microenvironment (TME). By overcoming limitations of therapies targeting a single-pathway (e.g., those targeting apoptosis), PANoptosis suppresses cancer progression, reverses drug resistance, and synergizes with radiotherapy through immune activation. Mechanistic insights are driving therapeutic strategies that target key regulators (ZBP1, RIPK3) and disease-specific miRNAs to modulate caspase-dependent and caspase-independent cascades. Its pathological duality-acute hyperactivation in tissue injury versus chronic dysregulation in degenerative diseases-highlights the need for context-dependent modulation. PANoptosis activation shows prognostic biomarker potential and universal therapeutic promise for drug-resistant cancers and inflammatory disorders, though clinical translation remains exploratory. This framework positions PANoptosis as a transformative paradigm bridging cell death dynamics and immune regulation.

Carnitine palmitoyltransferase 1A (CPT1A) has been implicated in the development of colorectal cancer (CRC), yet its role in ferroptosis remains to be fully understood. In this study, we found that CPT1A expression was associated with metastasis of CRC by gene datasets analysis and immunohistochemical staining of clinical samples, and it was upregulated in CRC cells compared with normal colon cell. The CCK-8, Transwell, and wound healing assays demonstrated that overexpression of CPT1A enhanced the viability, invasion, and migratory capacity of CRC cells. CPT1A expression was reduced following induction of ferroptosis in CRC cells, and this downregulation could be reversed by a ferroptosis inhibitor. Moreover, CPT1A overexpression inhibited ferroptosis in CRC cells. Nrf2, a well-known negative regulator of ferroptosis, was found to colocalize with CPT1A in CRC cells. Molecular docking, Co-IP assay and Ch-IP assay further confirmed an interaction between CPT1A and Nrf2. Notably, Nrf2 overexpression upregulated CPT1A expression, whereas Nrf2 knockdown produced the opposite effect. CPT1A overexpression led to activation of PI3K/AKT pathway in CRC cells. Inactivation of the PI3K/AKT pathway by the inhibitor partially reversed the anti-ferroptosis effect of CPT1A overexpression. Furthermore, inhibition of PI3K/AKT pathway suppressed Nrf2 expression, and reduce nuclear translocation of Nrf2, whereas activation of this pathway enhanced Nrf2 expression and nuclear translocation. In vivo experiments corroborated these findings, showing that CPT1A overexpression promoted Nrf2 expression, suppress ferroptosis, facilitated tumor growth, inactivated PI3K/AKT pathway. Taken together, our data suggest that CPT1A associates with metastasis of CRC, and inhibits ferroptosis through a regulatory feedback loop involving Nrf2 and PI3K/AKT pathway.

The mechanism underlying vascular remodeling in pulmonary arterial hypertension (PAH) involves complex interactions among various cell types, with dysregulation of endothelial cells (ECs) homeostasis considered a crucial pathological factor. However, their local cellular changes still need to be fully identified during PAH. This study utilized single-cell RNA sequencing data from the GEO database to analyze lung tissue samples from PAH patients and normal controls, revealing significant heterogeneity in lung ECs and dysregulated metabolic pathways. We identified a significant expansion of capillary ECs in PAH patients, linked to dysregulated angiogenesis and glycolysis-tricarboxylic acid cycle metabolic pathways. Through integrative high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning, we identified SPRY1 as a novel key biomarker in PAH pathogenesis and validated its significant downregulation in a monocrotaline-induced PAH rat model. These findings establish capillary ECs expansion and SPRY1 deficiency as pivotal drivers in PAH pathogenesis, providing a foundation for precise therapeutic targeting.

Programmed cell death has evolved from the classical concept of apoptosis to a diverse repertoire that includes necroptosis, pyroptosis, ferroptosis, cuproptosis, paraptosis, panoptosis, and even the reversal process of anastasis. These pathways have transformed our understanding of health and disease, influencing oncology, neurodegeneration, cardiovascular biology, infection, and immunity. Reflecting this growth, Apoptosis has reached a record Impact Factor of 8.1 in 2024, underscoring both the rising impact of cell death research and the journal's role as its central forum. This success reflects a community effort of authors, reviewers, and editorial board members, and highlights how programmed cell death continues to shape the future of biology and medicine.