Search Results (2,594)

Per- and polyfluoroalkyl substances (PFAS) continue to be one of the most persistent global contaminants and are increasingly recognized as leading metabolic- and hepatic-dysfunction mediators. Despite extensive investigation of PFAS toxicity, a critical gap in the identification and integration of toxicokinetic drivers of hepatic bioaccumulation with mechanistic pathways driving mitochondrial and nuclear receptor-related injury, more specifically, with respect to alternative PFAS strategies, still remains. Legacy PFAS, including PFOA and PFOS, accumulate in the liver and disturb mitochondrial homeostasis as they disrupt β-oxidation, induce oxidative stress, and alter lipid and bile acid metabolism. Meanwhile, the next-generation PFAS variants (including short-chain and polymeric substitutes) are rapidly increasing in environmental concentrations, but remain insufficiently characterized and poorly regulated, raising concerns that substitution-based strategies may maintain their toxicological risk. We summarize the evidence of the association between PFAS bioaccumulation and mitochondrial dysfunction, metabolic reprogramming, and inflammatory signaling, and illustrate mechanistic convergence across legacy and emerging PFAS. We also review insights from recent experimental models, such as 3D hepatocyte systems and human-relevant receptor platforms that more closely mimic chronic exposure states. This review emphasizes mechanistic convergence across legacy and emerging PFAS, highlighting shared pathways that may persist despite chemical substitution. Thus, we discuss key gaps in monitoring, toxicity assessment, and policy, including the requirement of regulatory paradigms that treat PFAS as a class rather than individual compounds. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated disease characterized by chronic, non-suppurative, small-duct lymphocytic cholangitis. The prognosis largely depends on early disease recognition and treatment. Suboptimal response to first-line therapy (ursodeoxycholic acid) is associated with risk for disease progression. Reliable biomarkers are also required to enhance risk stratification. The traditional gold standard for assessing fibrosis is liver biopsy, but it is invasive and unsuitable for serial evaluations. Hence, trends are towards non-invasive surrogate biomarkers (blood-based and imaging biomarkers respectively) which have a much better safety profile. Blood-based biomarkers include: (i) Fibrosis-4 [Fib-4], (ii) Aspartate Aminotransferase to Platelet Ratio Index [APRI], (iii) Enhanced Liver Fibrosis score [ELF], and (iv) total bile acid to platelet ratio [TPR]. They show much potential but are not particularly sensitive tests. Ultrasound-based imaging biomarkers are increasingly being utilized for liver stiffness measurement (LSM), with vibration-controlled transient elastography (VCTE) emerging as the preferred technique. However, despite its growing popularity, VCTE is limited by technical issues. Hence, currently, none of the non-invasive tests fulfill the prerequisites to be the new gold standard as defined by the FDA. Nonetheless, there may be value to combining LSM with various serum biomarkers such as Fib-4, APRI, as aforementioned. The hope is to create nomograms for predicting liver-related events and decision tree algorithms. Newer studies are investigating microbiota in the gut-liver axis, biomolecules such as nanovesicles/nanofibers, and metabolic reprogramming as it pertains to e.g., proteomics and lipidomics. These approaches hold much promise, and if validated, could significantly change the management of PBC. Full article

Trained immunity confers protection against subsequent unrelated infections through metabolic and epigenetic reprogramming. Unlike adaptive immunity, trained innate immunity provides broad, non-specific protection against diverse heterologous pathogens. In addition to potentiating inflammatory responses upon secondary challenge, trained innate immune cells can also acquire anti-inflammatory and tolerogenic phenotypes, a property with important implications for chronic inflammatory diseases such as allergic disorders. Trained immunity-based vaccines (TIbVs) have emerged as promising immunomodulatory strategies capable of attenuating allergic inflammation by inducing immune tolerance. Similarly, allergen-specific immunotherapy (AIT) promotes long-term tolerance to allergens through metabolic and epigenetic reprogramming of innate immune cells. AIT drives the differentiation of monocytes into tolerogenic dendritic cells, thereby reshaping downstream adaptive immune responses. This review summarizes the current understanding of trained immunity and its role in protection against the same and heterologous infections. We discuss the molecular mechanisms underlying trained immunity, with an emphasis on metabolic and epigenetic reprogramming. Furthermore, we highlight the therapeutic potential of TIbVs and AIT as next-generation vaccines for allergic diseases. A deeper understanding of AIT-induced immune tolerance, the identification of predictive biomarkers, and the optimization of delivery platforms—such as lipid nanoparticle-based systems—will be critical for improving the safety and efficacy of future anti-allergy vaccines. Full article

The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases. Full article

The sodium–hydrogen exchanger-1 (NHE1) is a ubiquitously expressed transmembrane transporter that plays a central role in maintaining intracellular pH homeostasis and supporting normal cellular function. In cancer, NHE1 is overexpressed in many tumor types and has been associated with increased cancer cell metastasis and proliferation. Beyond these established roles, emerging evidence implicates NHE1 as a regulator of cancer cell metabolism. By driving intracellular alkalinization and shaping the tumor microenvironment, NHE1 influences metabolic pathway activity, mitochondrial function, redox balance, and cellular stress responses. In this review, we synthesize current evidence linking NHE1 dysregulation to metabolic reprogramming in cancer, with a focus on mitochondrial metabolism, glycolytic flux, lysosomal biology, and reactive oxygen species-associated stress pathways. We further evaluate pharmacological strategies targeting NHE1, emphasizing their metabolic consequences, translational potential, and the challenges that have limited clinical application to date. Collectively, this review highlights NHE1 as a potential integrator of ion transport and metabolic control in cancer and discusses how targeting NHE1-driven metabolic programs may support the development of novel therapeutic strategies. Full article

Psoriasis, a chronic inflammatory skin disease, is driven by immune dysregulation and keratinocyte hyperproliferation, with current biologics facing limitations. Emerging evidence points to mitochondrial dysfunction and a pathological shift to aerobic glycolysis as core disease drivers. Here, we report that MitoFu-O, a novel mitochondria-targeting TPP-thiazole derivative, effectively ameliorates psoriasiform inflammation in imiquimod-induced mice and cytokine-stimulated keratinocytes. Mechanistically, MitoFu-O acts by inhibiting pathological glycolysis, downregulating key glycolytic enzymes (HK1, GAPDH, LDHA), and subsequently suppressing the activation of pivotal pro-inflammatory signaling pathways (MAPK, NF-κB, and STAT3). Our findings establish targeted mitochondrial modulation as a potent therapeutic strategy, positioning MitoFu-O as a promising lead compound that acts upstream of cytokine signaling by normalizing the metabolic reprogramming fundamental to psoriatic pathogenesis. Full article

As a novel form of cell death, the discovery of cuproptosis presents significant opportunities and challenges for the field of cancer therapy. Notably, polyphenolic compounds have attracted considerable research attention for their ability to induce cuproptosis. These natural compounds not only exhibit marked anti-inflammatory and antioxidant properties, but their polyhydroxy structures also enable effective chelation and transport of copper ions. This provides novel insights into cuproptosis-mediated cancer therapy. Therefore, in this review, we systematically outline copper metabolism, the mechanisms of cuproptosis, and its association with cancer, while providing an in-depth discussion of the effects and mechanisms by which polyphenolic compounds act as copper ionophores to inhibit tumor growth and progression through the induction of cuproptosis. This review indicates the promising potential of polyphenolic compounds in the field of cancer therapy and provides a theoretical basis for therapeutic strategies based on cuproptosis. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC. Full article

The maturation of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) remains a major translational bottleneck in regenerative cardiac medicine, as current differentiation platforms yield electrophysiologically and metabolically immature phenotypes. This review explores emerging strategies to engineer “smart” biomaterial interfaces that actively instruct iPSC-CM maturation through synergistic biophysical and metabolic reprogramming. By integrating nanotopographical patterning, mechanoelectric coupling, and tunable substrate stiffness with metabolic interventions such as mitochondrial substrate optimization and fatty acid oxidation induction, the literature reveals consistent links between cell–matrix crosstalk, sarcomeric organization, calcium handling, and oxidative metabolism. Recent advances in bioactive scaffolds and extracellular vesicle (EV)-functionalized hydrogels are highlighted as platforms capable of approximating key features of the myocardium’s native electromechanical and bioenergetic environment. Across two- and three-dimensional culture systems, this review identifies recurring maturation patterns, persistent gaps in metric standardization and long-term phenotype stability, and ongoing limitations related to scalability and translational implementation. Collectively, the findings synthesized here indicate that convergence between biomaterial engineering and metabolic programming represents a critical design principle for advancing iPSC-CMs toward functionally mature, clinically relevant phenotypes. This integrated approach enhances the fidelity of iPSC-CMs for disease modeling, drug screening, and regenerative cardiac therapies. Full article

Pollen development is a complex process that is highly sensitive to environmental stresses. Abscisic acid (ABA), a key hormone mediating plant growth and stress responses, has been implicated in the regulation of sexual reproduction, especially pollen development, yet its precise regulatory role remains unclear. This study investigated the effects of exogenous ABA on Arabidopsis thaliana pollen development and function through integrated phenotypic, cytological, and transcriptomic approaches. ABA treatment specifically impaired pollen function by reducing germination rates and inhibiting pollen tube elongation, which resulted in shortened siliques and decreased seed set, without affecting pollen morphology or viability. Transcriptome analysis of mature anthers revealed a transient and time-dependent transcriptional response, with the number of differentially expressed genes (DEGs) peaking at 8 h post-ABA treatment and markedly declining by 22 h. These DEGs were enriched in stress-response pathways (e.g., salt, cold, and dehydration), hormone signaling, and carbohydrate metabolism. Moreover, we identified 25 differentially expressed transcription factors and 16 pollen development and function-related genes, highlighting their key roles in ABA-mediated regulation. In parallel, 146 differentially expressed lncRNAs (DELs) were identified, which formed 144 cis-regulatory pairs with genes involved in ABA response and pollen tube growth, with their predicted targets enriched in pathways such as hormone and MAPK signaling, carbohydrate metabolism and stress response. Trans-regulatory analysis further revealed that these DELs co-expressed with DEGs in modules enriched for stress response, pollen development, and tube growth pathways. Notably, key pollen function genes showed strong co-expression with DELs, indicating that lncRNAs participate in ABA-induced transcriptional reprogramming that shifts metabolic resources from growth to defense, thereby suppressing pollen germination and tube elongation. Together, these findings elucidate a coordinated regulatory network involving mRNAs, lncRNAs and transcription factors roles in modulating ABA responses during pollen/anther development. Full article

During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) shift their lineage commitment away from osteogenesis and towards adipogenesis, resulting in bone loss and marrow fat accumulation. We previously reported that during osteogenesis, BMSCs activate mitochondrial oxidative phosphorylation (OXPHOS) at least in part by downregulating cyclophilin D (CypD) expression and, consequently, mitochondrial permeability transition pore (MPTP) activity. We also reported that in contrast, during adipogenesis, BMSCs upregulate CypD and MPTP, activate glycolysis and inhibit OXPHOS. To further study the role of CypD in BMSC bioenergetics, adipogenesis and bone marrow fat accumulation, we used CypD loss-of-function (LOF) or gain-of-function (GOF) models in osteo-adipoprogenitors in vitro and in vivo. We found that CypD LOF and GOF are associated with impaired and enhanced BMSC adipogenesis, respectively, both in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomic analyses show evidence of corresponding metabolic reprogramming in CypD LOF and GOF cells. In summary, our study demonstrates the role of CypD-regulated mitochondrial metabolism during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and the molecular mechanism of age-related bone loss as well as bone marrow fat accumulation. Full article

Mitochondrial dysfunction profoundly alters cellular metabolism, yet its systems-level consequences remain incompletely characterized. Here, we present a comprehensive untargeted metabolomics analysis of respiratory-deficient (ρ⁰) and competent (ρ⁺) Saccharomyces cerevisiae prototrophic cells using ultra-high-performance liquid chromatography coupled to Orbitrap Fusion™ Tribrid™ high-resolution mass spectrometry. By integrating hydrophilic interaction and reversed-phase chromatography in both ionization modes, we detected ~7000 features per chromatographic condition, of which ~12% were structurally annotated through MSⁿ fragmentation and in silico spectral matching. Principal component analysis revealed distinct metabolic signatures between ρ⁰ and ρ⁺ cells, with ~73% of total variance explained by the first two components. Volcano plot and hierarchical clustering analyses identified a marked accumulation of phosphate-containing metabolites, sphingolipids, ceramides, and fatty acid residues in ρ⁰ cells, whereas amino acids, excluding arginine, cysteine, and aromatics, were enriched in ρ⁺ cells. Notably, branched-chain amino acid depletion in ρ⁰ cells correlated with impaired growth and mitochondrial stress. Pathway enrichment analysis, supported by transcriptomic integration, prompted us to further investigate reprogramming of polyamine biosynthesis and aromatic amino acid metabolism. Calibration curves constructed from certified standards validated the accuracy of the LC–MS platform and reinforced annotation confidence. Our findings demonstrate that advanced untargeted metabolomics, coupled with MS³ fragmentation and multi-omics integration, enables high-resolution mapping of metabolic reconfiguration under mitochondrial dysfunction, offering mechanistic insights into mitochondrial retrograde signaling and adaptation. Full article

HER2-positive breast cancer accounts for 15–20% of all breast cancers. The introduction of anti-HER2 therapies has markedly improved the clinical outcomes; however, overcoming drug resistance in metastatic disease remains a major challenge. This review summarizes the multilayered mechanisms of resistance to trastuzumab and pertuzumab and outlines the rationale for sequential treatment strategies based on the emerging evidence. Resistance arises through diverse and often coexisting mechanisms, including structural alterations in the HER2 receptor (e.g., p95HER2 and HER2 mutations), constitutive activation of the PI3K–AKT–mTOR pathway, and engagement of bypass signaling through receptors such as HER3 and IGF-1R, as well as immune evasion and metabolic reprogramming. Given this complexity, the strategic sequencing of agents with distinct mechanisms of action is critical beyond first-line therapy. Trastuzumab deruxtecan demonstrates substantial antitumor activity through potent cytotoxic effects and a bystander effect, supporting its efficacy in tumors with intratumoral heterogeneity or downstream pathway activation. In contrast, tucatinib-based regimens represent an important option for patients with brain metastases and tumors expressing p95HER2. The ongoing development of novel antibody–drug conjugates and bispecific antibodies is expected to further advance personalized sequential therapy targeting composite resistance mechanisms. Full article

Background: Hepatocellular carcinoma (HCC) stands as a prevalent global health issue with increasing incidence and mortality rates. Hepatocellular carcinoma (HCC) exhibits profound molecular and clinical heterogeneity, which limits the effectiveness of current therapeutic strategies. Circadian rhythm disruption has been implicated in metabolic reprogramming, proliferation, and immune modulation in cancer, but its role in shaping HCC heterogeneity remains poorly defined. Methods: Four public HCC transcriptomic cohorts (TCGA-LIHC, CHCC, LIRI, LICA) were integrated using RMA normalization and ComBat for batch correction. Consensus clustering based on 31 core circadian clock genes (CCGs) identified robust molecular subtypes. Multi-omics characterization—including genomic alterations, pathway activity (GSEA/GSVA), immune microenvironment profiling (CIBERSORT, EPIC, MCP-counter, xCell), and drug-sensitivity prediction (pRRophetic/oncoPredict)—was performed to delineate subtype-specific biological properties. A nine-gene CCG-based RiskScore model was constructed using LASSO Cox regression to internally validate subtype robustness and intra-subtype risk stratification. Results: Using consensus clustering of 31 core CCGs in TCGA-LIHC and three independent validation cohorts (CHCC, LIRI, LICA), we identified three reproducible subtypes—Cluster-1 (metabolic–quiescent), Cluster-2 (transition–intermediate), and Cluster-3 (proliferation–inflammatory)—which were recapitulated across cohorts and showed distinct overall survival (Cluster-3 worst; log-rank p values significant across datasets). Multi-omic characterization revealed that Cluster-3 exhibits the highest tumor mutational burden and CNV burden with enrichment of TP53/AXIN1/TERT alterations, strong activation of cell-cycle, E2F, and G2M programs, and an immune-hot yet immunosuppressed microenvironment enriched for TAMs, Tregs and MDSCs. By contrast, Cluster-1 shows relative genomic stability, dominant hepatic metabolic signatures (fatty-acid oxidation, bile-acid and xenobiotic metabolism) and an immune-cold phenotype. Single-cell mapping linked ALAS1 expression to malignant hepatocytes predominating in Cluster-1, whereas NONO and CSNK1D localized to stromal (CAFs/TECs) and both malignant/immune compartments respectively in Cluster-3, providing a cellular mechanism for subtype-specific metabolism, angiogenesis and immune modulation. Finally, a nine-gene CCG-based RiskScore validated prognostic stratification and drug-sensitivity predictions indicated subtype-specific therapeutic vulnerabilities (notably increased predicted TKI sensitivity in Cluster-3). Conclusion: In conclusion, this study proposes a robust circadian rhythm-based molecular classification of hepatocellular carcinoma, revealing three biologically and clinically distinct subtypes characterized by divergent genomic alterations, metabolic programs, immune microenvironment states, and prognostic patterns. By integrating bulk and single-cell transcriptomic data, we identify subtype-specific roles of key circadian regulators—including ALAS1, NONO, and CSNK1D—in shaping tumor metabolism, proliferation, stromal remodeling, and immune suppression. These findings highlight circadian dysregulation as a potential upstream factor associated with HCC heterogeneity and provide a conceptual framework for developing subtype-tailored mechanistic studies and circadian-informed therapeutic strategies. Full article

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibility remains limited by the low prevalence of HRD mutations. In this review, we summarize the molecular mechanisms of PARPi action, resistance pathways, and emerging combination strategies. PARPi resistance arises through HR restoration (e.g., BRCA1/2 reversion mutations), replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming. Combination therapies, integrating PARPi with histone deacetylase inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint blockade, or radiation, enhance efficacy by converging on DNA repair pathways and the tumor immune microenvironment. A deeper understanding of coordinated DDR regulation and rationally designed combination regimens will be essential for overcoming PARPi resistance and advancing adaptive, precision-based therapeutic strategies. Full article