Frontiers in Cell and Developmental Biology最新文献

{"title":"PI3K/AKT/mTOR signaling at the immune checkpoint interface in lung cancer: molecular mechanisms, Tumor-Immune remodeling, therapeutic resistance, and emerging treatment strategies.","authors":"Hongliang Jin, Fan Yang, Shi Zong, Wenli Sun","doi":"10.3389/fcell.2026.1952310","DOIUrl":"https://doi.org/10.3389/fcell.2026.1952310","url":null,"abstract":"<p><p>Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have substantially improved the treatment of lung cancer, yet durable responses remain limited by primary and acquired resistance. Increasing evidence identifies the PI3K/AKT/mTOR pathway as a central link between oncogenic signaling, metabolic adaptation, and tumor immune suppression. Genetic and molecular alterations, including PIK3CA activation, PTEN loss, and aberrant EGFR or ALK signaling, can activate this pathway and regulate PD-L1 expression at transcriptional, translational, and post-translational levels. Conversely, tumor-intrinsic PD-L1 signaling can reinforce PI3K/AKT/mTOR activity, promoting proliferation, survival, glycolysis, epithelial-mesenchymal transition, and resistance to therapy. This reciprocal interaction establishes a feedforward circuit that supports lung cancer progression and immune escape. The pathway also reshapes the tumor microenvironment by promoting regulatory T-cell expansion, M2-like macrophage polarization, myeloid-cell recruitment, CD8⁺ T-cell dysfunction, and resistance to immune checkpoint blockade. This review critically examines the bidirectional crosstalk between PI3K/AKT/mTOR and PD-1/PD-L1 signaling in lung cancer and summarizes the molecular regulators that connect these pathways. We further discuss therapeutic strategies designed to disrupt this network, including PI3K, AKT, and mTOR inhibitors; targeted therapies; chemotherapy and radiotherapy combinations; antiangiogenic approaches; nanomedicine; extracellular-vesicle-based delivery; cell-based interventions; and natural compounds. Although preclinical evidence supports combining pathway inhibition with immune checkpoint blockade, clinical translation is challenged by pathway complexity, context-dependent regulation of PD-L1, systemic toxicity, and the absence of validated predictive biomarkers. Biomarker-guided patient selection, optimized dosing and sequencing, and selective targeting of tumor- or immune-cell-specific pathway components will therefore be essential for converting this mechanistic rationale into durable clinical benefit.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1952310"},"PeriodicalIF":5.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAFLD and impaired bone formation in children: association with reduced serum LCAT.","authors":"Lingyan Zhu, Lin Xu, Lanshu Yang, Baolan Sun, Weixia Yang","doi":"10.3389/fcell.2026.1902360","DOIUrl":"https://doi.org/10.3389/fcell.2026.1902360","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate bone metabolism indicators and serum lecithin-cholesterol acyltransferase (LCAT) levels in children with metabolic dysfunction-associated fatty liver disease (MAFLD), and to explore their interrelationship.</p><p><strong>Patients and methods: </strong>This study enrolled 127 children aged 6-14 years, classified into control (n = 42), obesity without hepatic steatosis (n = 41), and MAFLD (n = 44) groups. All participants underwent clinical evaluation, laboratory testing, and liver ultrasonography. Serum LCAT was quantified by enzyme-linked immunosorbent assay (ELISA). Bone turnover markers, including procollagen type I N-terminal propeptide (PINP), β-C-terminal telopeptide of type I collagen (β-CTX), and 25-hydroxyvitamin D [25-(OH) D], were measured via electrochemiluminescence. Independent risk factors for impaired bone formation were analyzed using multivariable ordinal logistic regression.</p><p><strong>Results: </strong>Serum LCAT concentrations were highest in controls (58.27 ± 4.43 mg/L), followed by obesity without hepatic steatosis (46.13 ± 3.37 mg/L), and lowest in the MAFLD group (40.71 ± 3.44 mg/L) (<i>P</i> < 0.001). The proportion of children with PINP below the 25th percentile was significantly greater in the MAFLD group (88.64%) than in obesity (48.78%) and control groups (35.71%) (<i>P</i> < 0.001). Significant intergroup differences were observed for 25-(OH) D, PINP values, PINP grade, and PINP/β-CTX ratio; PINP grade distribution differed among groups (<i>P</i> < 0.001), whereas β-CTX grade did not. Spearman analysis revealed significant correlations of LCAT with HDL-C, AST, ALT, fatty liver status, 25-(OH) D, and PINP grade (all <i>P</i> < 0.001). Multivariable ordinal logistic regression identified MAFLD (<i>OR</i> = 4.74, 95% CI: 1.41-15.99, <i>P</i> = 0.012) and older age (<i>OR</i> = 1.38, 95% CI: 1.08-1.75, <i>P</i> = 0.009) as independent factors associated with lower PINP grade, whereas LCAT was not independently associated with PINP grade.</p><p><strong>Conclusion: </strong>MAFLD was independently associated with lower PINP status in children. Reduced serum LCAT levels were associated with MAFLD and unfavorable bone formation status but were not independently associated with PINP grade after multivariable adjustment. LCAT may therefore represent an associated biomarker within the liver-bone axis, requiring validation through prospective studies, formal mediation analyses, and mechanistic experiments.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1902360"},"PeriodicalIF":5.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated lipidomic and transcriptomic profiling of imiquimod-induced psoriasiform dermatitis.","authors":"Eva Wisniewski, Wenwen Du, Jenna A Himelstein, Gergő Szanda, Taylor J Woodward, Ken Mackie, Heather B Bradshaw","doi":"10.3389/fcell.2026.1881695","DOIUrl":"https://doi.org/10.3389/fcell.2026.1881695","url":null,"abstract":"<p><p>Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Emerging clinical and experimental evidence suggests that endogenous lipid (endolipid) signaling systems, including the endocannabinoid system (ECS), represent a promising therapeutic target to treat psoriasis; however, comprehensive characterization of small-molecule endolipids and related proteins in psoriatic skin and their relationship to systemic changes remains limited. Here, we used the imiquimod (IMQ)-induced mouse model of psoriasis to perform combined lipidomic and transcriptional profiling of endolipid signaling in both skin and plasma. Targeted lipidomics revealed a striking divergence between tissues: most endolipids increased in inflamed skin but decreased in plasma, including the canonical ECS lipids anandamide and 2-arachidonoylglycerol. In contrast, selected lipid species, including taurine-conjugated metabolites (both <i>N</i>-acyl taurines and bile acids), were elevated in both tissues, indicating pathway-specific regulation. Targeted transcriptional analysis of whole skin showed reduced expression of key endolipid biosynthetic enzymes (<i>Napepld, Dagla, Daglb</i>) and the cannabinoid receptor <i>Cnr1</i>, while <i>Cnr2</i> and ECS-related metabolic enzymes remained unchanged. Additional alterations were observed in transcripts involved in related endolipid signaling (<i>Trpv1, Trpv4, Ppara, Pparg, Gpr55</i>), bile acid metabolism (<i>Fxr, Bsep, Fabp4, Fabp5, Cyp27a1, Cyp8b1</i>), and inflammatory pathways (<i>Cox-2</i>). To resolve this apparent discrepancy between lipid levels and gene expression, we performed compartment-specific analyses of epidermal and dermal layers. These revealed a predominantly suppressive epidermal response across multiple ECS-related proteins, contrasted by a more variable dermal profile with selective preservation or upregulation, particularly of <i>Cnr2</i>. Together, these findings demonstrate that psoriasiform inflammation is associated with compartment-specific remodeling of endolipid signaling across skin and systemic compartments, underscoring the functional heterogeneity of epidermal and dermal layers. This dataset provides novel insights into the dysregulation of endolipid signaling systems in psoriasis and provides a foundation for the development of spatially informed, lipid-based therapeutic strategies.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1881695"},"PeriodicalIF":5.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular metabolomics reveals the osteogenic mechanism of MC3T3-E1 cells in porous Ti6Al4V scaffolds under low-intensity pulsed ultrasound.","authors":"Xinyun Li, Lin Wu","doi":"10.3389/fcell.2026.1945138","DOIUrl":"10.3389/fcell.2026.1945138","url":null,"abstract":"<p><strong>Introduction: </strong>Porous titanium alloy scaffolds offer multiple advantages in treating large-area bone defects; however, their poor bioactivity limits their application. Low-intensity pulsed ultrasound (LIPUS) serves as a non-invasive method to enhance bone regeneration in porous titanium-6aluminium-4vanadium (Ti6Al4V) alloy scaffolds. This study aimed to examine the biological behavior and metabolism of murine osteoblastic MC3T3-E1 cells in porous Ti6Al4V (pTi64) scaffolds under LIPUS.</p><p><strong>Methods: </strong>MC3T3-E1 cells were incubated in pTi64 scaffolds and stimulated with LIPUS. Cell morphology, viability, and osteogenic-related gene expression were evaluated <i>in vitro</i>. Intracellular metabolites of MC3T3-E1 cells incubated in pTi64 scaffolds and stimulated with LIPUS for 7 days were analyzed using an ultraperformance liquid chromatography coupled with a triple quadrupole-linear ion trap mass spectrometer (UPLC-QTRAP-MS)-based cellular metabolomics approach.</p><p><strong>Results: </strong><i>In vitro</i>, MC3T3-E1 cells in the pTi64+LIPUS group exhibited enhanced morphology, viability, and osteogenic-related gene expression compared with the pTi64 group, suggesting that LIPUS enhances cell morphology, reduces apoptosis, and promotes osteogenic differentiation in pTi64 scaffolds. LIPUS treatment altered the cellular metabolic network; 86 differential metabolites were identified. Alterations in metabolic pathways were associated with the one-carbon pool by folate, pantothenate and coenzyme A biosynthesis, as well as the metabolism of amino acids, glycerolipids, and arachidonic acid.</p><p><strong>Discussion: </strong>These findings offer novel insights into the osteogenic mechanisms of MC3T3-E1 cells in pTi64 scaffolds under LIPUS.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1945138"},"PeriodicalIF":5.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of cementoblasts in root resorption induced by orthodontic treatment: from mechanosensation to repair potential.","authors":"Yue Feng, Yanling Xie, Xing Hu, Zhiqiao Qiu, Shuixue Mo","doi":"10.3389/fcell.2026.1953825","DOIUrl":"10.3389/fcell.2026.1953825","url":null,"abstract":"<p><p>While alveolar bone has high remodeling activity under physiological conditions, cementum has a strong antiresorptive capacity. Cementoblasts are the primary functional and mechanosensitive cells on the cementum surface that maintain the structural homeostasis of the tooth root. However, excessive or sustained orthodontic force applied during treatment often induces irreversible orthodontically induced inflammatory root resorption (OIIRR), characterized by impaired cementoblast function and defective root surface repair. Although the precise molecular mechanisms underlying cementoblast dysfunction and the progression of root resorption under orthodontic force remain incompletely understood, posing major challenges for the prevention and management of OIIRR, orthodontic force-induced programmed cell death and secretory dysregulation in cementoblasts are known to hinder the self-repair of resorption lacunae, thereby exacerbating root tissue destruction. Consequently, intervention strategies-including physical therapy, pharmacological therapy, and biomaterial-based approaches-targeting the biological properties of cementoblasts are being developed to reactivate their differentiation and mineralization potential and promote functional repair of the root surface. This review provides a comprehensive overview of the biological role of cementoblasts in orthodontic root resorption and repair, establishing a theoretical basis and providing new insights for the development of cementoblast-targeted strategies to prevent and treat OIIRR.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1953825"},"PeriodicalIF":5.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial proteomics: technical evolution and applications in cancer research.","authors":"Xiaoxiao Tian, Di Huang, Jiaxiang Hu","doi":"10.3389/fcell.2026.1914317","DOIUrl":"10.3389/fcell.2026.1914317","url":null,"abstract":"<p><p>Spatial proteomics is reshaping tissue-based cancer research by linking protein expression to cellular identity, tissue architecture and clinical behavior. Conventional proteomics has provided powerful tools for protein identification and quantification, but most bulk workflows erase the spatial relationships that define tumor ecology. In contrast, spatial proteomics combines multiplexed imaging, mass spectrometry-based tissue analysis, region-selected profiling and computational spatial statistics to measure proteins in their native tissue context. This review summarizes the development of proteomics from early separation and mass spectrometry technologies to current spatial platforms. It then focuses on cancer applications, including tumor heterogeneity, tumor microenvironment, antitumor immunity, immunotherapy response, spatial biomarkers and treatment resistance. Across these areas, spatial proteomics is most valuable when it converts descriptive tissue patterns into testable hypotheses about cell states, neighborhood interactions and therapeutic vulnerabilities. The field now needs standardized workflows, clinically anchored cohorts and functional validation to move from high-dimensional tissue maps to robust translational tools.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1914317"},"PeriodicalIF":5.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Geno-guided targeting of ferroptosis: a multi-layered network to overcome radioresistance in lung cancer.","authors":"Shifang Sang, Guangchao Lv, Shiyun Feng, Hui Zhao, Yulong Ren, Dianlong Jin, Kaizhong Wang","doi":"10.3389/fcell.2026.1886712","DOIUrl":"10.3389/fcell.2026.1886712","url":null,"abstract":"<p><p>Lung cancer is one of the most prevalent and lethal malignancies worldwide, and radiotherapy serves as a standard therapeutic modality for the management of advanced or inoperable non-small cell lung cancer. However, radioresistance remains a major obstacle that compromises therapeutic efficacy and drives tumor recurrence. Ferroptosis-an iron-dependent, lipid peroxidation-governed form of regulated cell death-substantially contributes to radiation-mediated tumor cell elimination. This review establishes a multi-layered regulatory network through which ferroptosis mediates radioresistance in lung cancer, spanning genetic mutations, epigenetic and RNA-based regulation, protein post-translational modifications, and lipid metabolism reprogramming. Unlike existing reviews, this paper stratifies ferroptotic vulnerability and radiosensitivity according to common driver genotypes-including TP53, LKB1and KEAP1-and proposes a genotype-guided paradigm for precise radiosensitization. By integrating these molecular layers, review provides a supplementary theoretical framework for optimizing radiotherapy in lung cancer and highlights how targeting ferroptosis can overcome resistance in a mutation-specific manner. Furthermore, the crosstalk between ferroptosis and cuproptosis represents a promising combinatorial therapeutic avenue that warrants further preclinical and clinical investigation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1886712"},"PeriodicalIF":5.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo-YAP/TAZ signaling in inner ear development, injury, and regeneration: evidence synthesis and the biomechanical brake hypothesis.","authors":"Dongmei Guan, Xinghong Liu, Xiaoyi Zhang, Jingqi Zhang, Hui Xie","doi":"10.3389/fcell.2026.1878367","DOIUrl":"10.3389/fcell.2026.1878367","url":null,"abstract":"<p><p>Sensorineural hearing loss in mammals is essentially irreversible. Mature cochlear hair cells, once lost, do not regenerate. Non-mammalian vertebrates retain this ability, but in the mammalian organ of Corti, supporting cells lose their proliferative and transdifferentiation competence after birth. Reactivation of classical developmental pathways has also shown limited success in the adult cochlea. In this review, we first synthesize published evidence on Hippo-Yes-associated protein(YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in the inner ear, including studies of inner-ear progenitors, organ of Corti growth, vestibular sensory epithelia, cochlear hair-cell injury, neonatal cochlear regeneration models, and emerging adult cochlear data. On this basis, we then evaluate the biomechanical brake hypothesis, which proposes that injury-associated mechanical remodeling may interact with Hippo-YAP/TAZ signaling to restrict supporting-cell plasticity in the mature mammalian cochlea. Rather than presenting this hypothesis as an established mechanism, we treat it as an evidence-graded framework that must be tested against alternative explanations, including protective epithelial repair, cell-cycle inhibition, epigenetic restriction, and loss of developmental competence. The available literature suggests that Hippo-YAP/TAZ signaling participates in several inner-ear processes, including progenitor expansion, sensory epithelial growth, species-dependent vestibular repair, otoprotective responses, and supporting-cell proliferation under defined experimental conditions. However, direct evidence that injury-induced mechanical remodeling causally suppresses YAP/TAZ-dependent regeneration in the adult cochlea remains limited. We therefore distinguish among developmental, neonatal, vestibular, <i>ex vivo</i>, and adult <i>in vivo</i> evidence, and identify where current findings support, weaken, or remain insufficient to establish the biomechanical brake model. Finally, we outline specific gaps that should guide future work: comprehensive tabulation of Hippo-related inner-ear studies, adult supporting-cell lineage tracing, spatial mapping of cochlear mechanical properties and Hippo activity, cell-subtype-specific perturbation of YAP/TAZ signaling, functional assessment by auditory brainstem response and distortion product otoacoustic emission, and long-term evaluation of epithelial stability. This organization is intended to clarify what Hippo-YAP/TAZ signaling has already been shown to do in the inner ear, what remains speculative, and which experiments are required before mechanobiological modulation can be considered a plausible regenerative strategy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1878367"},"PeriodicalIF":5.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron, lipid peroxidation and discogenic pain: a redox framework for ferroptosis in intervertebral disc degeneration.","authors":"Qiyun Shi, Xiaotong Xu, Shen Zhai, Jitian Li, Yongwei Song","doi":"10.3389/fcell.2026.1938559","DOIUrl":"10.3389/fcell.2026.1938559","url":null,"abstract":"<p><p>The weak correlation between radiographic disc degeneration and pain intensity remains unresolved in intervertebral disc degeneration (IVDD). This Review proposes that iron-dependent lipid peroxidation and ferroptosis-associated redox signalling constitute an underrecognised link between degenerative stress and a pro-nociceptive disc microenvironment. Two linked frameworks are developed. The pro-ferroptotic niche integrates four disc-specific mechanisms: Piezo1-mediated iron influx, ferroportin suppression, ferritinophagy mediated by the cargo receptor NCOA4, and glycolysis-derived lactate upregulating the PUFA-activating enzyme ACSL4. ALOX15-coupled lipid peroxidation rests mainly on cross-disease inference. The ferroptotic pain hub proposes that resulting damage-associated signals, including the alarmin HMGB1 and 4-hydroxynonenal, may converge on NF- <math><mrow><mi>κ</mi></mrow> </math> B-dependent induction of NGF, BDNF, and IL-6. Relevant receptor-level signalling is supported in disc cells, whereas the ferroptosis-specific coupling remains untested. Intervention is organised into four tiers: iron handling, antioxidant-reserve restoration, lipid-peroxidation blockade, and damage-signal-NF- <math><mrow><mi>κ</mi></mrow> </math> B interruption. Deferoxamine and N-acetylcysteine are discussed as an illustrative, unvalidated multi-tier combination, with translation constrained by the need for disc-adapted delivery, intradiscal pharmacokinetic/pharmacodynamic characterisation, local safety assessment, and pain-endpoint validation. Disc-specific evidence, cross-disease inference, mechanistic inference, and hypothesis-level prediction are distinguished throughout, with falsifiable tests defined. The aim is not to present ferroptosis as a proven cause of discogenic pain, but to offer a testable framework for mechanism-based stratification of painful IVDD.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1938559"},"PeriodicalIF":5.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics integration identifies Acsm2/ACSM2A deficiency as a metabolic driver of ZBP1-mediated PANoptosis in acute kidney injury.","authors":"Lijuan Lu, Yuping Qin","doi":"10.3389/fcell.2026.1936504","DOIUrl":"10.3389/fcell.2026.1936504","url":null,"abstract":"<p><p>Acute kidney injury (AKI) converges on tubular epithelial cell (TEC) death and metabolic collapse, fueling the transition to chronic kidney disease (CKD), yet the molecular link between metabolic failure and inflammatory cell death remains poorly defined. Here, we integrated cross-model transcriptomics of three mechanistically distinct murine AKI models with single-cell RNA-seq, high-dimensional weighted gene co-expression network analysis, and machine learning feature selection. This multi-omics framework identified acyl-CoA synthetase medium-chain family member 2 (Acsm2), a rate-limiting mitochondrial enzyme for medium-chain fatty acid β-oxidation, as the top conserved hub gene suppressed in injured proximal tubule cells. Acsm2/ACSM2A downregulation was confirmed in mouse AKI models and in human HK-2 cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R). ACSM2A deficiency alone was sufficient to simultaneously activate apoptosis, pyroptosis, and necroptosis, indicative of PANoptosis, whereas restoration of ACSM2A expression attenuated OGD/R-induced cell death. Mechanistically, <i>ACSM2A</i> loss provoked mitochondrial oxidative stress and drove the accumulation of Z-form nucleic acids. Scavenging mitochondrial reactive oxygen species or silencing ZBP1 rescued cells from <i>ACSM2A</i> knockdown-induced cell death, implicating ZBP1 as a downstream mediator. Collectively, our findings establish <i>ACSM2A</i> loss as a trigger of ZBP1-dependent PANoptosis in TECs and position the ACSM2A-ZBP1 axis as a candidate pathogenic mechanism that warrants further investigation as a potential therapeutic node for intercepting the AKI-to-CKD transition.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1936504"},"PeriodicalIF":5.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}