Nuclear lamins organize the structural and regulatory architecture of the nucleus, integrating nuclear mechanics, chromatin organization, and genome regulation. During cardiac development, lamin composition undergoes a coordinated transition that parallels the shift from proliferative embryonic cardiomyocytes to mechanically active postnatal cells. Recent findings reveal that B-type lamins support early nuclear plasticity and proliferative capacity, whereas Lamin A/C stabilizes nuclear architecture and transcriptional programs in mature cardiomyocytes. Beyond their structural roles, lamins participate in multiple layers of nuclear regulation, including lamina-associated chromatin organization, nucleo–cytoskeletal mechanotransduction, nucleocytoplasmic transport, and regulation of mitotic progression and cell-cycle exit. Through these interconnected functions, the nuclear lamina coordinates cardiomyocyte proliferation, maturation, and mechanical stress adaptation during heart development. Mutations in lamin genes cause a diverse group of disorders collectively known as laminopathies, many of which prominently affect the cardiovascular system. In this review, we first examine how B-type and A-type lamins are developmentally deployed to regulate cardiomyocyte proliferation and maturation in the heart. We then discuss the mechanistic pathways through which lamins organize nuclear architecture, chromatin dynamics, and nucleo–cytoskeletal signaling to coordinate cardiac cellular function. Finally, we consider how disruption of these lamin-dependent regulatory networks contributes to cardiomyopathy, cardiovascular aging, and the loss of regenerative capacity in the adult mammalian heart.

HighlightsWhat are the main findings?Direct comparison of mitochondrial ROS production in human and rat cardiac and skeletal muscle revealed species-specific differences in dominant ROS sources: complex I (RET) predominated in humans, whereas complex III (IIIQo) was the major source in rats.When normalized to respiratory activity, human mitochondria exhibited a greater relative capacity for ROS production at complex I, while ROS generation at complex III remained comparatively lower than in rat tissues.What are the implications of the main findings?These results challenge the assumption that ROS production patterns observed in rodent models directly translate to human physiology.Species-specific differences in mitochondrial ROS generation may influence the effectiveness of cardioprotective strategies targeting oxidative stress, highlighting the need for human-focused approaches.Mitochondrial reactive oxygen species (ROS) play a central role in cardiac ischemia/reperfusion injury, heart failure, and arrhythmogenesis, while also serving essential signaling functions under physiological conditions. Among the eleven identified mitochondrial ROS-producing sites, complexes I and III are considered the major contributors, particularly under conditions of impaired electron flow. However, much of the existing knowledge comes from rodent models or cultured cells and is often assumed to apply to humans. Here, ROS production from complexes I and III was measured directly in human myocardial and skeletal muscle biopsies and compared with corresponding rat tissues under identical experimental conditions. Hydrogen peroxide generation was quantified using Amplex UltraRed, with simultaneous monitoring of mitochondrial respiration using a Clark-type oxygen electrode. Across all examined mechanisms—reverse and forward electron transport at complex I and the ubiquinol oxidation site of complex III, rat tissues produced more ROS than human tissues, consistent with their higher respiratory rates. However, the dominant ROS-producing sites differed: in rats, complex III was the primary source, whereas in human tissues the highest ROS production occurred during reverse electron transport at complex I. When normalized to respiration, human tissues showed relatively greater ROS generation at complex I but markedly lower production at complex III. These direct measurements of mitochondrial ROS production in human myocardium provide new insight into cardiac redox physiology and may explain the limited clinical translation of cardioprotective strategies targeting mitochondrial ROS production, such as interventions aimed at modulating reperfusion injury or preconditioning.

Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy–neuroinflammation axis in neurodegenerative disorders.

HighlightsWhat are the main findings?PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK pathways coordinately regulate key steps of the metastatic cascade in TNBC.TNBC molecular heterogeneity is linked to differential activation of signaling networks driving EMT, invasion, and metastatic colonization.What are the implications of the main findings?Mapping pathway activity to specific metastatic stages provides a mechanistic framework for interpreting TNBC progression.Targeting signaling dependencies associated with TNBC subtypes may support the development of more precise therapeutic strategies.Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC.

HighlightsWhat are the main findings?Radiotherapy can induce ferroptosis through ROS-driven lipid peroxidation and antioxidant disruption.Ferroptosis susceptibility strongly influences radiosensitivity and radioresistance in head and neck cancers.Targeting lipid metabolism, iron homeostasis, and the SLC7A11–GPX4 axis enhances radiation-induced ferroptosis.What are the implications of the main findings?Ferroptosis induction represents a promising strategy to radiosensitize resistant head and neck tumors.Tumor-selective ferroptosis modulation may widen the therapeutic ratio of radio-therapy.Integrating ferroptosis biology with radiotherapy and immunotherapy could improve treatment outcomes.Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and failure of cellular antioxidant defenses. Increasing evidence indicates that ferroptosis contributes to the biological effects of radiotherapy and influences both tumor radiosensitivity and normal tissue injury. Because radiotherapy is a central treatment modality for many head and neck cancers, understanding how ferroptosis interacts with radiation responses has important translational implications. Ionizing radiation can induce ferroptosis through reactive oxygen species generation, disruption of glutathione metabolism, suppression of the SLC7A11–GSH–GPX4 antioxidant axis, and remodeling of membrane lipid composition. Conversely, tumor cells frequently develop radioresistance by reinforcing ferroptosis-suppressive pathways, including enhanced cystine transport, lipid desaturation, and metabolic adaptation. In head and neck cancers such as head and neck squamous cell carcinoma, nasopharyngeal carcinoma, oral squamous cell carcinoma, and thyroid malignancies, experimental studies show that modulation of ferroptosis significantly alters radiation response. Strategies that promote ferroptosis—including inhibition of antioxidant defenses, targeting of lipid metabolism, and modulation of iron homeostasis—have demonstrated radiosensitizing effects in preclinical models. However, ferroptosis may also contribute to radiation-induced normal tissue injury, particularly in oxidative stress-sensitive organs such as the salivary glands. This review summarizes the molecular basis of ferroptosis in radiotherapy, examines its role in radiosensitivity and radioresistance in head and neck cancers, and discusses therapeutic strategies to exploit ferroptosis while minimizing normal tissue toxicity.

Glypican-3 (GPC3)-targeted chimeric antigen receptor T (CAR-T) cell therapy is a promising approach for hepatocellular carcinoma (HCC), but marked interpatient variability and antigen heterogeneity limit its broader application. Here, we established a patient-derived organoid (PDO)-based platform to functionally evaluate autologous GPC3-targeted CAR-T cell activity in HCC. HCC PDOs preserved key histologic features and heterogeneous GPC3 expression patterns of the original tumors. In co-culture assays, CAR-T cell cytotoxicity was associated with GPC3 expression levels and was accompanied by IFN-γ and IL-2 release, supporting the feasibility of using PDOs for functional assessment of CAR-T cell sensitivity. We further found that matrix conditions strongly influenced organoid architecture, viral transduction, CAR-T cell infiltration, and killing efficiency, with lower Matrigel concentrations providing a more permissive setting for functional assessment. Importantly, in GPC3-low PDOs, pretreatment with the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) reduced DNA methyltransferase 3 alpha (DNMT3A) expression, increased surface GPC3 expression, and significantly enhanced CAR-T-mediated cytotoxicity. Together, these findings provide proof-of-concept evidence supporting the use of HCC PDOs as a patient-derived platform for modeling selected determinants of GPC3-targeted CAR-T cell activity and for exploring combination strategies to improve therapeutic efficacy.

HighlightsWhat are the main findings?Keloids and hypertrophic scars are increasingly recognized as immune-driven fibroproliferative disorders rather than isolated abnormalities in wound healing.Dysregulation of immune signaling pathways involving cytokines like IL-6, TNF-α, TGF-β and IL-17 contributes to prolonged inflammation and fibroblast activation.What are the implication of the main findings?Targeting immune–fibrotic signaling feedback loops represents a promising therapeutic approach beyond conventional scar-directed treatments.Emerging therapies aimed at modulating immune pathways can improve long-term outcomes and reduce recurrence rates.Keloids and hypertrophic scars are fibroproliferative disorders of wound healing characterized by excessive extracellular matrix deposition, constant inflammation, and high recurrence rates despite appropriate management. Conventional therapies, including surgical excision, corticosteroid injections, laser therapy, and radiation, can provide temporary relief. However, treatment failure remains common, specifically in refractory keloids. Recent findings suggest these outcomes cannot be fully explained by technical or mechanical factors alone, and pathological scarring may reflect underlying immune and neuroimmune dysfunction. Current evidence shows prolonged activation of pro-inflammatory and pro-fibrotic cytokine pathways like IL-6, TNF-α, TGF-β, and IL-17 drives sustain fibroblast activation and disrupts normal wound healing and remodeling. Additionally, the skin functions as an integrated neuro-endocrine-immune organ, allowing bidirectional communication between cutaneous nerves, immune cells, and stromal tissue. Neurogenic inflammation is mediated by neuropeptides, mast cell activation, and stress-induced hypothalamic–pituitary–adrenal axis dysregulation, which further amplifies inflammation within scar tissue. Psychiatric comorbidities like depression, anxiety, and chronic psychological stress serve as a positive feedback mechanism and are increasingly recognized as biologically active contributors to immune dysregulation. This review highlights critical gaps in current management strategies and emphasizes the need for biologically informed, multidisciplinary approaches to improve long-term outcomes for keloid and hypertrophic scar management.

HighlightsWhat are the main findings?FOXM1 is upregulated in MCL and it correlates with a worse clinical outcome.FOXM1 and NFκB form a positive feedback loop.What are the implications of the main findings?Inhibiting FOXM1 decreases the growth and drug resistance of MCL cells.FOXM1 represents a potential therapeutic target in MCL.Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) cytogenetic abnormality and cyclin D1 overexpression. We have found evidence that Forkhead box M1 (FOXM1), a transcription factor with oncogenic potential, is important in the pathogenesis of MCL. Relatively high levels of FOXM1 proteins were detectable in all six MCL cell lines examined. By immunohistochemistry, we consistently found a subset of FOXM1-positive cells in MCL tumors. Analysis of two Gene Expression Omnibus (GEO) datasets from MCL patients showed that elevated FOXM1 levels significantly correlate with a worse clinical outcome. In MCL cell lines, inhibition of FOXM1 using thiostrepton or shRNA effectively triggered apoptosis and significantly reduced cell growth. FOXM1 forms a positive feedback loop with NFκB in MCL cells. Specifically, inhibition of FOXM1 dramatically decreased the protein level/transcription activity of p65, while enforced FOXM1 expression upregulated p65 and downregulated IκBα, a key NFκB inhibitor. Conversely, curcumin-mediated NFκB inhibition decreased the protein level/DNA binding of FOXM1, while transduction of a constitutively active IKKα construct into MCL cells significantly dampened the inhibitory effects of thiostrepton. Confocal microscopy revealed that FOXM1 and p65 colocalize with each other. In conclusion, FOXM1 and NFκB work collaboratively in promoting the growth and drug resistance of MCL, and FOXM1 may be a potentially useful therapeutic target.

Myocardial infarction (MI) triggers a robust inflammatory response that is essential for tissue repair but, when excessive or prolonged, drives pathological cardiac remodelling and heart failure. Colony-stimulating factor 2 (CSF2) signalling has been implicated in driving pro-inflammatory macrophage activation post-MI. Here, we investigated the role of macrophage-specific CSF2 receptor alpha (CSF2RA) signalling in post-MI remodelling using a tamoxifen-inducible genetic mouse model and permanent coronary artery ligation. Macrophage-specific Csf2ra deficiency significantly improved left ventricular systolic function post-MI without altering cardiac fibrosis burden. Functional improvement was associated with enhanced collagen scar maturation, characterised by an increased proportion of mature collagen fibres, and with accumulation of anti-inflammatory, pro-reparative macrophages within the infarct. These macrophage changes were accompanied by increased fibroblast density, consistent with altered macrophage–fibroblast crosstalk. Collectively, these findings identify macrophage-intrinsic CSF2RA signalling as a critical regulator of inflammatory resolution and scar maturation after MI and provide mechanistic support for the rationale of selective CSF2RA inhibition as a therapeutic strategy to limit adverse cardiac remodelling and improve post-infarction recovery.

HighlightsWhat are the main findings?Glycolysis in cancer is not merely upregulated but dynamically rewired across different stages of tumorigenesis, with early metabolic changes actively contributing to malignant transformation rather than passively supporting tumor growth.Glycolytic rewiring integrates anabolic metabolism, redox homeostasis, and epigenetic regulation, and is continuously remodeled by transcriptional, post-translational, and microenvironmental inputs during tumor progression.What are the implications of the main findings?Viewing glycolysis as a dynamic and stage-specific regulatory network provides a more comprehensive framework for understanding tumor metabolism and its role in coordinating multiple cancer-associated processes.The context-dependent metabolic dependencies generated by glycolytic rewiring highlight new opportunities for therapeutic targeting, particularly through strategies that exploit redox imbalance, metabolic plasticity, and combinatorial vulnerabilities.Glycolysis is a defining feature of cancer metabolism, originally described by the Warburg effect. Increasing evidence indicates that cancer-associated glycolysis is not uniformly upregulated but dynamically rewired in response to oncogenic signaling, cellular demands, and microenvironmental cues. However, a framework integrating its temporal evolution and functional roles across tumorigenesis remains limited. In particular, how glycolytic rewiring drives malignant transformation, adapts during tumor progression, and generates context-dependent vulnerabilities has not been systematically synthesized. In this review, we examine glycolysis as a dynamic metabolic network evolving throughout tumor development. We discuss how early glycolytic rewiring, driven by oncogenic signaling and metabolic–epigenetic coupling, supports cell fate transitions and establishes redox and biosynthetic capacity during tumorigenesis. We then outline how glycolysis is remodeled during tumor progression through coordinated transcriptional, epigenetic, and post-translational regulation, as well as microenvironmental interactions and metabolic heterogeneity. Furthermore, we highlight glycolysis as an integrative hub linking immune evasion, cell death regulation, and metabolic plasticity, and discuss how glycolytic rewiring creates context-dependent metabolic dependencies that may be therapeutically exploited, along with emerging technologies that enable high-resolution characterization of tumor metabolism. Together, this review provides a conceptual framework for understanding glycolytic rewiring in cancer and outlines potential avenues for targeting metabolic vulnerabilities.