Previous transcriptomic analysis revealed that eicosapentaenoic acid (EPA) alters miRNA expression in HepG2 cells. Two key miRNA-mRNA axes mediating EPA's antioxidant effects were identified. EPA was found to downregulate let-7c-3p, which directly targets mitochondrial transcription factor A (TFAM). Inhibiting let-7c-3p or overexpressing TFAM enhanced antioxidant capacity, reduced reactive oxygen species, improved mitochondrial function, and promoted mitochondrial biogenesis. In parallel, EPA was found to upregulate miR-34c-5p, which directly targets NAD-Dependent Protein Deacetylase Sirtuin (SIRT1). This repression of SIRT1 is associated with increased activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. These findings indicate a dual-miRNA mechanism through which EPA alleviates oxidative stress via coordinated enhancement of mitochondrial biogenesis and enzymatic defenses.
In the nervous system, aging causes deterioration of cellular and molecular processes that are associated with declines in cognition, sensory perception, and motor coordination. Aging is also the strongest risk factor for neurodegenerative disease, yet the mechanisms by which aging predisposes neurons to dysfunction remain incompletely understood. While genomic instability, proteostasis decline, mitochondrial dysfunction, and chronic inflammation have dominated prevailing models, recent evidence highlights RNA dysregulation as a central component of age-associated decline. In this review, we summarize recent findings suggesting that aging progressively erodes RNA regulatory fidelity through alterations in RNA-binding protein abundance, localization, biophysical behavior, and RNA interactions. We argue that age-dependent RNA dysregulation represents an important mechanism that converges with genetic risk to drive neuronal vulnerability and neurodegeneration.
The spindle assembly checkpoint (SAC) promotes mitotic fidelity by delaying anaphase until all kinetochores are stably attached to spindle microtubules. SAC silencing is increasingly recognised as a dynamic, sensitive process involving multiple molecular events at individual kinetochores. In Cell Reports, Conway et al. reveal how these events sequentially unfold.
Discovered in the 1970s, nuclear lamins control chromatin organization and are linked to many diseases. Zhang et al. now find that lamin A/C quantitatively constrains DNA replication initiation by limiting chromatin accessibility and sequestering proliferating cell nuclear antigen, extending lamin's long-known role in replication to the control of origin firing.
Ferroptosis is a form of programmed cell death characterized by iron-dependent phospholipid peroxidation and is implicated in a wide range of human diseases. Emerging evidence highlights the critical role of epigenetic regulation in this process. Dysregulation of histone post-translational modifications (HPTMs) is increasingly recognized as a pivotal mechanism linking metabolic reprogramming to various pathological conditions. HPTMs constitute one of the key epigenetic regulatory mechanisms and mediate ferroptosis by modulating the transcription of core ferroptosis-related genes. This review systematically summarizes site-specific HPTMs, including histone methylation, acetylation, ubiquitination, phosphorylation, lactylation, and β-hydroxybutyrylation. Furthermore, we elucidate how infectious diseases, tumors, and chronic non-infectious conditions drive disease progression via HPTMs-dependent regulation of ferroptosis. A comprehensive dissection of these epigenetic regulatory networks may facilitate the development of combinatorial therapeutic strategies targeting HPTMs and ferroptosis inducers, thereby providing new insights into the treatment of ferroptosis-associated disorders.
Breast cancer is the most frequently diagnosed malignancy among women worldwide, with 2.3 million new cases and approximately 670,000 deaths reported in 2022 alone. Despite advances in therapy, metastasis and acquired drug resistance remain major clinical challenges. Reactive oxygen species (ROS) play a dual role in breast cancer biology: physiological levels sustain normal cellular signaling, moderately elevated levels promote tumorigenesis through DNA damage, proto-oncogene activation, and tumor suppressor inactivation, while excessive accumulation can trigger cancer cell death. This review examines how redox dysregulation contributes to breast cancer initiation and progression through key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), as well as apoptotic cascades. We evaluate the evidence for dietary and synthetic antioxidants-melatonin, curcumin, vitamins C and E, and carotenoids-as chemopreventive and adjuvant agents, highlighting both their therapeutic promise and the conflicting data on their safety during cancer treatment. We further discuss emerging ROS-responsive nanoagents for targeted drug delivery and immunotherapy, and strategies to exploit redox vulnerabilities in multidrug-resistant breast cancer cells, including induction of ferroptosis, an iron-dependent cell death pathway driven by lipid peroxide accumulation that has emerged as a promising vulnerability in therapy-resistant and mesenchymal-phenotype tumors. Recent advances in machine learning and multi-omics integration, which have begun to identify redox-related gene signatures with prognostic and immunotherapy-predictive value, further point toward precision redox oncology as an emerging clinically actionable framework. By integrating molecular mechanisms with translational advances, this review identifies current gaps and future directions for ROS-targeted therapeutic strategies in breast cancer.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown cause, marked by excessive deposition of extracellular matrix (ECM) components such as collagen. This pathological accumulation results in progressive destruction of the lung architecture and ultimately leads to respiratory failure. Growing evidence indicates that dysfunction across multiple cell types is an important driver of IPF. Nevertheless, its underlying pathobiology remains incompletely understood. The normal integrity of organelles is critical for cellular function, and in different IPF lung cells, such as alveolar epithelial cells (AECs), fibroblasts, and macrophages, we found dysfunctional development of key organelles and metabolic reprogramming changes driving malignant progression of pulmonary fibrosis. This review summarizes the contributions of key organelles-mitochondria, the endoplasmic reticulum, lysosomes, and peroxisomes-and functional changes in metabolic reprogramming during IPF progression. We further clarify the core mechanisms of how inter-organelle network disruptions drive fibrosis, with the goal of identifying critical organelle nodes to disrupt pathogenic metabolic reprogramming and ultimately provide a rationale for developing new treatments.
The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associated sorting of NAC53/78 toggles these transcription factors between ER-associated degradation and nuclear activation, coupling proteasome induction to repression of photosynthesis-associated genes during stress.
NHE-1 is a Na+/H+ exchanger that receives phosphorylation signals, binds calmodulin and responds to neurohormonal input from angiotensin II, endothelin-1, and adrenergic pathways. In cardiac myocytes, NHE-1 maintains pH homeostasis and couples to Na+/Ca2+ exchange and mitochondrial ion handling. During heart disease sustained activation drives intracellular Na+ accumulation, promoting Ca2+ overload and mitochondrial dysfunction. Oxidative stress then creates amplifying cycles that activate signaling pathways resulting to arrhythmias and fibrosis. Clinical trials failed despite preclinical promise, due to a variety of false experimental factors. SGLT2 inhibitors appear to modulate NHE-1 indirectly through metabolic reprogramming and hemodynamic effects rather than direct blockade. Current approaches use structural data to target regulatory sites and phosphorylation-dependent conformational states instead of the transport pore. Translation to patients will require biomarkers identifying pathological hyperactivity and better patient stratification methods. Here, we try to review NHE-1 structure, regulation, and physiology that may influence research on future drug development.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, as a key DNA sensor, plays a significant role in the regulation of innate immune responses. This pathway can be activated by sensing abnormal DNA, and is of great significance for resisting the invasion of pathogenic microorganisms and maintaining tissue homeostasis. In addition, the cGAS-STING pathway plays a dual role in cancer, and oncogenic viruses can cause cell carcinogenesis in the body through multiple mechanisms, thereby affecting human health. This manuscript reviews the vital role of cGAS-STING in the immune process, as well as the fact that viruses causing human tumor lesions can activate cGAS-STING, leading to virus inhibition and further preventing the occurrence and development of related cancers, and the paradoxically promoted progression of related cancers by viruses through cGAS-STING. And summarize the agonists and inhibitors that act in different ways based on the activation mechanism of cGAS-STING.
AKT (protein kinase B, PKB) coordinates the balance between anabolic and catabolic signaling in skeletal muscle through distinct ubiquitin chain types. Some E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) form stable binary complexes via non-catalytic interfaces, adding a regulatory layer unavailable to either enzyme alone. This mechanistic synthesis review presents a systematic literature analysis (inception to May 2026; 26 eligible studies). It identified four E3-DUB pairs proposed to regulate AKT in skeletal muscle. These are TRAF6-CYLD (plasma-membrane K63-ubiquitination), MUL1-USP9X (mitochondrial K48-ubiquitination of AKT2), CHIP-UCH37 (proteasome-proximal quality control), and SCF-Skp2-USP37 (PHLPP1/2-dependent control of AKT Ser473 phosphorylation). All four interfaces are structurally separate from the catalytic sites and are regulated by upstream kinase phosphorylation. Evidence for the four pairs is markedly uneven. TRAF6-CYLD is supported by endogenous co-immunoprecipitation and functional data in muscle models. CHIP and UCH37 each act on AKT-related substrates independently and are individually well documented, but a direct CHIP-UCH37 interaction has not itself been demonstrated. SCF-Skp2-USP37 interaction data rest on a real but non-muscle direct interaction, whereas MUL1-USP9X has no reported direct interaction at all; CHIP-UCH37, SCF-Skp2-USP37, and MUL1-USP9X are therefore all presented as testable hypotheses of varying strength. In chronic atrophy, available data are consistent with disruption of these complexes contributing to AKT suppression through parallel, largely independent mechanisms. However, simultaneous disruption of all four has not been demonstrated in a single system. Available gene expression and protein datasets from sarcopenic muscle broadly support these predictions, though direct experimental validation in human tissue remains pending. This complex-centric framework recasts AKT ubiquitination as an integrated regulatory framework. Each structurally autonomous interface may represent a potentially distinct target for muscle-wasting conditions that currently lack approved therapies.
The endothelial barrier provides a defense against bacterial pathogens. Muenkel et al. show that endothelial barrier function increases when macrophages interact with endothelial cells. Conversely, infected macrophages decrease endothelial barrier function and transmigrate more efficiently. These findings show that the endothelium is biomechanically responsive to the infection status of macrophages.
Nuclear CGAS has previously been shown to promote tumor progression by inhibiting DNA repair. Recent data from Zhang et al. demonstrate that, upon phosphorylation by PKCα, CGAS translocates to the nucleus and initiates a CTNNB1-dependent program supporting metastatic dissemination. Thus, nuclear CGAS emerges as a multifaceted driver of cancer progression.
Vitamins are essential micronutrients traditionally viewed as passive cofactors that sustain cellular homeostasis. Emerging evidence challenges this notion, identifying vitamins as active regulators of cell fate that tune the threshold for regulated cell death. Through coordinated control of redox balance, metabolic pathways, and signaling networks, vitamins shape cellular susceptibility to diverse death programs. Their effects are highly context-dependent, enabling both prosurvival and prodeath outcomes depending on dose, cell type, and metabolic state. Recent studies further uncover noncanonical mechanisms linking vitamins to lipid remodeling, membrane trafficking, and organelle integrity. Collectively, these advances establish vitamins as dynamic modulators of cellular vulnerability and highlight their potential as therapeutic targets for selectively manipulating cell death in disease.
Multiple myeloma (MM) is a malignant plasma cell disorder, and despite substantial improvements in prognosis achieved through chemotherapy, immunotherapy, and autologous stem cell transplantation, most patients ultimately develop relapsed or refractory disease. Drug resistance (DR) is increasingly recognized as a dynamically evolving ecosystem shaped by tumor-intrinsic plasticity and continuous remodeling of the bone marrow microenvironment (BMME), rather than as a single molecular lesion. This review summarizes the major mechanisms of resistance across key drug classes, including alterations in drug targets and signaling nodes, rewiring of apoptotic, proteostatic, and metabolic circuits, and BMME-dependent protection. We highlight how these processes converge on a limited set of survival hubs and collectively raise the apoptotic threshold under therapeutic pressure. The key to overcoming DR is to conceptualize it as an evolving ecosystem, thereby enabling rational, mechanism-based combination and sequencing strategies that may prolong progression-free survival and move MM closer to a functional cure.
Tuberculosis, caused by Mycobacterium tuberculosis (MTB), affects approximately 25% of people globally as latent infection (LTBI). Although macrophage CREB activation promotes MTB survival, the underlying mechanisms remain unclear. This study reveals, for the first time, how MTB modulates M2 macrophage polarization through the CREB1/TREM2 signaling pathway. Mononuclear macrophages were isolated from clinical sample. Flow cytometry was used to determine the M2 polarization ratio. The expression of TNF-α, IL-10, and IL-1β was determined by ELISA. The mRNA expression of iNOS, IL-1β, CD206, Arg-1, IL-10, CREB1, and TREM2 was assessed by qPCR. The protein expression of CREB1, CD206, Arg-1, IL-10, and TREM2 was evaluated by western blot. The colony-forming unit (CFU) assay was used to detect the survival of MTB. CHIP and Dual-luciferase reporter assays were used to confirm the binding of CREB1 and TREM2. Clinical sample analysis revealed that the expression levels of CREB1 and TREM2 in peripheral blood mononuclear macrophages (PBMCs) were significantly upregulated in tuberculosis patients. Following H37Rv infection, an increase in the M2 macrophage proportion was observed. Infection with MTB also elevated the protein level of IL-10, as well as CREB1 mRNA and protein expression. Transfecting sh-CREB1 into macrophages or adding CREB inhibitors 666-15 markedly reduced intracellular MTB CFU counts, implying a potential restrictive effect on viable MTB load within macrophages. Knockdown of TREM2 similarly decreased MTB CFU burden and restrained macrophage M2 polarization. Furthermore, transfecting sh-CREB1 into macrophages can suppress the proliferation of MTB within macrophages, and these effects could be further counteracted by the action of oe-TREM2. These results elucidated that MTB promoted M2 macrophage polarization through CREB1/TREM2.
Meningiomas exhibit marked biological heterogeneity that is not fully captured by current histopathological grading. Increasing evidence suggests that mitochondrial metabolism contributes to tumor aggressiveness; however, the molecular mechanisms regulating mitochondrial function in meningiomas remain poorly defined. Here, we investigated the role of mitochondrial transcription factor A (TFAM)-driven mitochondrial biogenesis and translation in meningioma progression. We performed integrative transcriptomic, immunohistochemical, and mitochondrial DNA analyses in a well-characterized cohort of 91 meningiomas, comprising World Health Organization grade 1 (G1) and grade 2 (G2) tumors with long-term clinical follow-up. RNA sequencing identified enrichment for mitochondrial metabolic pathways, including oxidative phosphorylation and ATP metabolism, that was preferentially activated in G2 meningiomas. TFAM and its upstream regulator PGC1α were significantly upregulated at both mRNA and protein levels in G2 tumors and exhibited a positive correlation, consistent with enhanced mitochondrial biogenesis. Although mitochondrial DNA copy number did not differ significantly between grades, G2 meningiomas showed a trend toward increased mitochondrial mass. Notably, G2 meningiomas demonstrated marked enrichment of mitoribosomal genes, including MRPL15, MRPL35, MRPL42 and MRPS22, whose expression correlated positively with TFAM and PGC1α expression levels. Network analysis identified TFAM as a central hub linking mitochondrial biogenesis, translation, and metabolic pathway activation. These findings were independently validated using a publicly available meningioma transcriptomic dataset. Together, our results reveal a TFAM-centered mitochondrial regulatory program that integrates mitochondrial biogenesis, translational capacity, and oxidative metabolism in higher-grade meningiomas. This mitochondrial translational axis represents a previously unrecognized mechanism underlying meningioma progression and highlights potential metabolic vulnerabilities for therapeutic intervention.
The role of microbes in cancer is gaining attention these days, especially in the context of tumor-associated biofilms and dysbiotic microbiota. Biofilm-producing microorganisms, such as Fusobacterium nucleatum and Helicobacter pylori, trigger oncogenic inflammation and immune evasion in tumor initiation and progression, and in the development of chemoresistance, through the activation of the NF-κB, STAT3, and β-catenin pathways. Dietary terpenoids are a structurally diverse group of antitumor and antibiofilm plant metabolites. Monoterpenoids, sesquiterpenoids, and triterpenoids are known to inhibit quorum sensing, the biosynthesis of extracellular polymeric substances (EPS), and the expression of biofilm-associated virulence factors, proposing an unexplored convergence among antibiofilm and anticancer mechanisms. Importantly, the biofilm structure (thickness, developmental stage, EPS density) affects the efficacy of terpenoids, affecting diffusion, microbial persistence, and therapeutic susceptibility. The quorum-sensing disruption is more effective in the early stages of biofilms, while high concentrations of EPS in mature, thick biofilms will require more penetration to disrupt quorum sensing. Innovative functional food matrices, including nano-enabled delivery systems, are emerging strategies to improve bioavailability and microbiome modulation of terpenoids. Furthermore, nano-formulations allow better penetration in dense biofilm matrices, protect terpenoids from early degradation, and allow prolonged and focused drug release in the tumor microenvironment associated with biofilms. Combining precision nutrition with microbiome-informed dietary strategies can be used to prevent and treat cancer. The present review combines studies linking biofilm-driven carcinogenesis with terpenoid-mediated antibiofilm-anticancer pathways and nano-mediated functional delivery and biofilm penetration, including highlighting the potential for microbiome modulation in cancer therapy.
