Glutaminolysis, the metabolic process of converting glutamine into key intermediates, plays an essential role in cellular energy production, signaling, biosynthesis, and redox balance. Deregulation of glutamine metabolism significantly influences various pathological conditions, including cancers and metabolic and neurological diseases. Emerging evidence shows that long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and oncogenic alterations in glutamine transporters and enzymes enhance glutamine's role as an alternative energy source, supporting cell survival and proliferation under nutrient and oxygen deprivation conditions. To combat the pathogenic effects of altered glutamine metabolism, researchers are developing targeted inhibitors of key enzymes and transporters involved in glutaminolysis. By interfering with the mechanisms that support the growth of cancer cells, these inhibitors may be able to stop the growth of tumors and treat metabolic and neurological conditions. This review provides a comprehensive overview of existing inhibitors and ongoing clinical trials targeting glutamine metabolism, focusing on its potential as a cancer therapeutic strategy. Additionally, the role of lncRNAs and circRNAs in regulating glutamine metabolism is explored, revealing novel avenues for therapeutic intervention in cancer and other diseases.

Biomarkers play a pivotal role in the detection and management of diseases, including obesity—a growing global health crisis with complex biological underpinnings. The multifaceted nature of obesity, coupled with socioeconomic disparities, underscores the urgent need for precise diagnostic and therapeutic approaches. Recent advances in biosciences, including next-generation sequencing, multi-omics analysis, high-resolution imaging, and smart sensors, have revolutionized data generation. However, effectively leveraging these data-rich technologies to identify and validate obesity-related biomarkers remains a significant challenge. This review bridges this gap by highlighting the potential of machine learning (ML) in obesity research. Specifically, it explores how ML techniques can process complex data sets to enhance the discovery and validation of biomarkers. Additionally, it examines the integration of advanced technologies for understanding obesity mechanisms, assessing risk factors, and optimizing treatment strategies. A detailed discussion is provided on the applications of ML in multi-omics analysis and high-throughput data integration for actionable insights. The academic value of this review lies in synthesizing the latest technological and analytical innovations in obesity research. By providing a comprehensive overview, it aims to guide future studies and foster the development of targeted, data-driven strategies in obesity management.

Later-line treatment has demonstrated limited survival benefits in patients with metastatic colorectal cancer (mCRC). This retrospective study evaluated the efficacy and safety of a triplet regimen combining metronomic capecitabine, antiangiogenic drugs, and PD-1 inhibitors in patients with mCRC. Between January 2021 and December 2023, 21 patients with mCRC received a triplet regimen as later-line treatment. Among these, seven patients achieved objective responses, nine had stable disease, two experienced disease progression, and three showed neither complete response nor progressive disease. The objective response rate (ORR) was 33.3% (7/21), and the disease control rate (DCR) was 90.5% (19/21). The median progression-free survival (PFS) was 5.4 months (95% CI, 4.8–6.0), and the median overall survival (OS) was 10.4 months (95% CI, 6.3–14.5). A total of 17 patients experienced treatment-related adverse events, including 9 with Grade 3/4 toxicities. After 1:1 propensity score matching, 42 patients (21 receiving the triplet regimen and 21 receiving other therapies) were included. The triplet regimen was associated with significantly improved PFS (5.4 vs. 2.7 months, p = 0.01) and OS (10.4 vs. 4.7 months, p = 0.04) compared with other therapies. In conclusion, the triplet regimen demonstrated promising antitumor activity and manageable toxicity in patients with refractory mCRC.

Molecular subtyping in diffuse large B-cell lymphoma (DLBCL) leads to facilitating drug selection. However, an integrated prognostic model based on molecular subtyping and clinical features has not been well established. Here, we retrospectively performed whole genome sequencing, whole exome sequencing, and fluorescence in situ hybridization in newly diagnosed DLBCLs, established a simplified LymphType algorithm for classification evaluation, and proposed a new integrated prognostic stratification system, combined molecular subtypes and International Prognostic Index (IPI) scoring system in our in-house sequencing cohort (N = 100), and validated in three public cohorts (N = 1480). Compared with IPI scoring system and classification algorithm model alone, the discrimination ability of prognostic model based on the new integrated model showed best discrimination of overall survival with concordance index value (0.773 vs. 0.724 vs. 0.648). We subsequently established a four-category risk model defined for the integrated prognostic model as follows: low, low-intermediate, high-intermediate, and high risk, demonstrating stronger prognostic separation across all end points (all p < 0.001) in our in-house cohort and three validation cohorts. Collectively, the new feasible integrated prognostic stratification system contributes to accurate prognosis assessment in clinical routine and provides a new basis for the follow-up treatment.

N6-methyladenosine (m6A), as the most common RNA modification at the post-transcriptional level, plays a role in various pathophysiological processes. However, its underlying mechanism in skin aging remains enigmatic. Here, we identified that fat mass and obesity-associated protein (FTO) serves as a protective factor against skin aging. FTO expression is downregulated in aging skin tissues and senescent fibroblasts. Furthermore, the depletion or inhibition of FTO exacerbates dermal fibroblasts senescence and accelerates skin aging. Additionally, RNA-seq combined with MeRIP-seq revealed that lysine acetyltransferase 8 (KAT8) is the downstream target of FTO. FTO deficiency leads to an increase in m6A levels and a decrease in mRNA stability of KAT8 in a m6A-YTHDF2-dependent manner. Notably, our integrated analysis of m6A sequencing and acetylation proteomics links changes in heterochromatin structure with aging. Mechanistically, KAT8 depletion leads to heterochromatin loss and the subsequent aging by acetylating remodeling and spacing factor 1 (RSF1) at K1050. Overall, our finding reveals a pivotal role of FTO-mediated m6A modification in the skin aging by regulating KAT8/RSF1-involved heterochromatin formation. It provides new insights into the mechanisms and strategies for delaying aging and improving healthspan.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and tissue damage, driven by dysregulated cytokine signaling and immune cell hyperactivation. Bruton's tyrosine kinase (BTK) mediates pathogenic B-cell activation and autoantibody production, while Janus kinase 3 (JAK3) orchestrates cytokine-driven inflammation through signal transducer and activator of transcription 5 (STAT5) phosphorylation, exacerbating macrophage and monocyte activation. Here, we report Wj1113, a novel dual inhibitor that potently blocks BTK (IC₅₀ = 0.7 nM) and JAK3 (IC₅₀ = 26.2 nM). Wj1113 inhibits B-cell activation via BTK blockade and suppresses JAK3-dependent STAT5 phosphorylation, reducing proinflammatory cytokine secretion and monocyte chemotaxis. In vitro, it suppresses macrophage activation and modulates inflammatory mediator expression. In the collagen-induced arthritis mouse model, Wj1113 treatment dose-dependently reduces joint inflammation, macrophage infiltration, and levels of TNF-α (tumor necrosis factor-α), IL(interleukin)-6, anti-cyclic citrullinated peptide antibody (ACPA) and rheumatoid factor (RF), while elevating anti-inflammatory IL-10. Histopathological and micro-CT analyses confirm attenuation of cartilage/bone erosion and synovial hyperplasia. Mechanistically, Wj1113 inhibits BTK/JAK3 signaling in vivo and alleviates arthritis in joints. Collectively, these findings establish Wj1113 as a promising dual-target therapeutic candidate for RA, addressing both B-cell and cytokine-driven pathogenic pathways.

A major obstacle to using current guideline-recommended chemotherapy in patients with advanced light-chain cardiac amyloidosis (LCCA) is their intolerance to standard drug dosages. The study aimed to assess the efficacy and safety of the dose-tailored BD and DBD regimen proposed by our team for patients with LCCA at Mayo Stage III. A total of 119 patients who met the inclusion and exclusion criteria for cardiac amyloidosis were recruited and divided into three groups: group A, group B, and group C who received supportive therapy, dose-tailored BD regimen, and dose-tailored DBD regimen, respectively. Survival rate and time, hematologic and cardiac response, and adverse events were evaluated during a median follow-up of 30.2 months. No significant differences in baseline characteristics were found among the three groups. Group B and C showed increased survival rates and time compared to group A. Group C showed improved hematologic and cardiac responses relative to group B. Additionally, group C showed fewer adverse events related to chemotherapy compared to group B. Both dose-tailored BD and DBD regimens increased survival rates and time in advanced LCCA patients, with the dose-tailored DBD regimen demonstrating superior efficacy and safety. Further randomized clinical trials are needed to confirm these preliminary findings.

Multiple sclerosis (MS) is an autoimmune disease causing neuroinflammation and demyelination in the central nervous system (CNS). It is traditionally considered CD4⁺ T cell-mediated, but several immune cells, such as CD8⁺ cells, B cells, macrophages, and dendritic cells (DC) also contribute to the pathogenesis. Moreover, altered gut microbiota, including changes in specific genera, has been observed in MS patients. The murine model of MS, experimental autoimmune encephalomyelitis (EAE), is mainly carried out in C57BL/6 mice. Historically, N and J substrains have been used interchangeably, and many laboratories are not even aware of which strain they are using. Therefore, the objective of this study was to evaluate the differences between the 6J and 6N substrains subjected to myelin oligodendrocyte glycoprotein (MOG_35–55) induced EAE in the composition of neuroinflammatory cells and microbiota. 6J substrain presented a more severe EAE than the 6N substrain, accompanied by an increase in the frequency of macrophages, CD8⁺, and B cells within the infiltrated immune cells compartment. In addition, 6J animals have a higher proinflammatory profile and a lower anti-inflammatory profile compared with the 6N substrain. Consistent with this, the differences observed in the basal microbial taxa between both substrains support the differences observed in the immunological response.

Pseudomonas aeruginosa (P. aeruginosa) infections pose a significant threat to public health, underscoring the need for deeper insights into host cellular defenses. This study explores the critical role of autophagy-related protein 5 (ATG5) in lung epithelial cells during P. aeruginosa infection. Single-cell RNA transcriptomics revealed a pronounced enrichment of autophagy pathways in type II alveolar epithelial cells (AEC2). Using a conditional Atg5 knockout murine model, we demonstrated that ATG5 deficiency in AEC2 compromises survival, hampers bacterial clearance, and increases pathogen dissemination. Additionally, the loss of ATG5 exacerbated inflammatory responses, notably through the activation of the AKT/PI3K/NF-κB axis and pyroptosis, which culminated in severe lung injury and epithelial barrier disruption. Mechanistically, the absence of ATG5 disrupted mitophagy, leading to intensified mitochondrial damage. This exacerbated condition coupled with the activation of gasdermin D (GSDMD) by the noncanonical caspase-11, enhancing the release of mitochondrial DNA (mtDNA), which in turn activated cGAS–STING–NLRP3 signaling in macrophages. These findings highlight the essential role of ATG5 in modulating immune responses and suggest potential therapeutic targets for managing P. aeruginosa-induced pulmonary infections.

Integrating bioinformatics tools has profoundly transformed precision oncology by identifying essential molecular targets for personalized treatment. The rapid development of high-throughput sequencing and multiomics technologies creates complex datasets that require robust computational methods to extract meaningful insights. Nonetheless, the clinical application of multiomics data continues to pose significant challenges. This review explores advanced bioinformatics tools utilized within multiomics, emphasizing their pivotal role in discovering cancer biomarkers. Cloud-based platforms, such as Galaxy and DNAnexus, facilitate streamlined data processing, while single-cell analysis software, including Seurat, identifies rare cellular subpopulations. Further integration of artificial intelligence with machine learning approaches improves predictive modeling and diagnostic accuracy. Spatial omics technologies correlate molecular signatures within tumor microenvironments, guiding treatment strategies. Bioinformatics integrates these technologies to establish a new standard in precision oncology, thereby enhancing therapy efficacy. Collaborative initiatives between The Cancer Genome Atlas and cBioPortal expedite advancements through the sharing open data and implementing standardized methodologies. Advancing multiomics integration techniques alongside improved computational capabilities is essential for discovering new biomarkers and refining precision medicine strategies. Future efforts should focus on merging multiomics techniques with innovative computational methods to drive novel biomarker discovery and improve precision medicine applications.

Ten-eleven translocation (TET) family proteins are Fe(II)- and α-ketoglutarate-dependent dioxygenases, comprising three family members: TET1, TET2, and TET3. These enzymes drive DNA demethylation by sequentially oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine. Through these reactions, TET proteins remodel the epigenetic landscape and interact with transcription factors and RNA polymerase II to regulate gene expression, cell lineage specification, and embryonic development. Mutations and dysregulation of TETs have been associated with the pathogenesis of various diseases, including the nervous system, immune system, and metabolic diseases, as well as cancers. Therapeutic modulation of TETs may be an effective strategy for the treatment of these diseases. Here, we provide a comprehensive overview of the mechanisms by which TET proteins mediate DNA demethylation and detail their biological functions. Additionally, we highlight recent advances in understanding the molecular mechanisms linking TET dysregulation to disease pathogenesis and explore their potential as therapeutic targets. This review supplements the current understanding of the critical role of epigenetic regulation in disease pathogenesis and further facilitates the rational design of targeted therapeutic agents for diseases associated with mutations and dysregulation of TETs.

Organs dynamically interact with each other through immunomodulation to create a systemic immune response and influence disease progression. While traditional studies have tended to focus on single-organ immunity, recent studies have placed greater emphasis on reciprocal immune interactions between organs, such as those between the gut, liver, and brain. However, the precise mechanisms underlying these interorgan immune interactions remain unclear. Here, we synthesize the molecular and cellular bases of cross-organ immune regulation in the context of inflammation and neoplasia. Specifically, we describe the immune coordination between the gut, liver, and brain and how they immunomodulate other organs (including the thyroid, lung, cardiovascular system, kidney, bone, and skin). In addition, we explore clinical therapies that target these cross-organ immune modulations, the limitations of the treatments, and the potential benefits for patients. We also conclude by highlighting innovative technologies such as multiomics analysis, machine learning, and organ-on-a-chip platforms, which are providing unprecedented insights into interorgan immunity. Elucidating these mechanisms will advance precision medicine and enable the development of targeted therapies for diseases caused by cross-organ immunity.

Mutations in mitogen-activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from Garcinia bracteata. Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)-mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA-seq results indicated that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib-induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR-149-5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N-acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment.

Recently, rapidly evolving STING-based immunotherapies have offered novel therapeutic options for various cancer types. However, systemic administration of STING agonists raises safety concerns, and intratumoral injection is constrained by tumor accessibility. Herein we developed an immune-stimulating antibody conjugate (ISAC) that links STING agonists to antibodies that target HER2-positive tumor cells via a cleavable linker. In vivo studies demonstrated that the STING agonist ISAC is well tolerated and exhibits potent antitumor activity in syngeneic mouse tumor models. Investigations in STING-knockout HER2-positive tumor cells and STING-knockout mouse models revealed that the STING pathway primarily mediates antitumor effects upon the activation of immune and tumor cells and that the activation of immune cells plays a stronger role. Additionally, our findings indicate that the STING agonist ISAC enhances both innate and adaptive antitumor immune responses, leading to sustained antitumor activity and the establishment of immune memory. These outcomes support the clinical development of the STING agonist ISACs.

Animal studies have shown that osteocalcin (OCN), a hormone derived from bone, plays a vital role in brain development and cognitive function. However, its potential connection to Alzheimer's disease (AD) pathology in humans remains largely unexplored. This cross-section study included 238 cognitively unimpaired participants, 26 mild cognitive impairment (MCI) patients, 54 AD dementia patients, and 32 patients with non-AD neurodegenerative diseases. Plasma and cerebrospinal fluid (CSF) levels of OCN were measured by enzyme-linked immunosorbent assay kits. In the clinical diagnosis-based subgroup, plasma and CSF levels of OCN were significantly higher in MCI and AD dementia compared with cognitively unimpaired participants. In the ATN framework-based subgroup, plasma and CSF OCN levels were significantly elevated in Aβ-positive participants, including those in the preclinical stage of AD. Both plasma and CSF OCN levels were negatively correlated with CSF Aβ42 and positively correlated with CSF total-tau and phosphorylated-tau181/Aβ42. In addition, OCN mediated the relationship between Aβ pathology and tau pathology. Notably, OCN levels in plasm and CSF were also negatively associated with cognitive functions. This study provides clinical evidence linking OCN to AD, suggesting that OCN may be associated with brain Aβ deposition, tau hyperphosphorylation and neurodegeneration.

Macrophages exhibit remarkable functional plasticity by dynamically polarizing into proinflammatory or antiinflammatory subsets in response to microenvironmental cues. This duality underpins their pivotal roles in immune defense, tissue homeostasis, and disease progression; however, the molecular mechanisms governing their polarization and crosstalk across various pathologies remain incompletely defined. This review systematically delineates macrophage biology, emphasizing the interplay between subset-specific signaling networks and their context-dependent activation in both health and disease. The heterogeneity of macrophages is characterized by detailing the distinctions between tissue-resident and monocyte-derived origins, as well as their polarization states. Core pathways regulating phagocytosis, tissue repair, immune modulation, and neuroprotection are dissected, along with their dysregulation in autoimmune disorders, neurodegeneration, cancers, and cardiovascular diseases. Notably, microenvironmental factors such as damage-associated molecular patterns, pathogen-associated molecular patterns, and metabolic intermediates dynamically reshape macrophage phenotypes through NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation or signal transducer and activator of transcription (STAT)-mediated transcriptional control. Preclinical and clinical evidence underscores potential therapeutic targets and emerging strategies. The significance of this review lies in its integrative analysis of signaling crosstalk, paradoxical pathway roles, and translational implications for precision therapies. These insights into macrophage functions and signaling pathways provide a robust foundation for future disease intervention and personalized medicine.

Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that play a pivotal role in diverse cellular processes and are extensively implicated in the pathophysiology of various diseases. Here, we provide a comprehensive overview of snoRNAs, encompassing their classification, biogenesis, and both canonical and noncanonical functions. Canonical roles include guiding RNA modifications such as 2′-O-methylation, pseudouridylation, and N4-acetylcytidine modification in targeted RNA molecules, as well as facilitating ribosome biogenesis. Noncanonical roles involve regulating mRNA processing, modulating alternative splicing, generating snoRNA-derived small RNAs, and interacting with long noncoding RNAs. Dysregulation of snoRNAs has been implicated in various human diseases, such as cancer, neurodegenerative disorders, cardiovascular diseases, immunity- and inflammation-related conditions, and aging, highlighting their potential as diagnostic and prognostic biomarkers. Advances in high-throughput sequencing, structural biology, and bioinformatics tools have significantly contributed to the detection, screening, and exploration of the intricate biofunctions of snoRNAs. However, despite these technological advancements, challenges remain in unraveling the biological complexity of snoRNAs and translating these findings into clinical applications. This review discusses the current state of snoRNA research, recent technological breakthroughs, and future directions, emphasizing their emerging roles in health and disease.

Proteolysis targeting chimeras (PROTACs) have emerged as a groundbreaking class of anticancer therapeutics. These bifunctional molecules harness the endogenous ubiquitin–proteasome system to facilitate the degradation of targeted proteins of interest (POIs). Notably, the clinical translation of PROTACs has gained substantial momentum, with many PROTAC candidates targeting various cancers currently undergoing clinical trials (Phase I–III). However, the rational design of high-efficacy PROTAC compounds remains a significant challenge. In this review, we presented a comprehensive overview of POI ligands, E3 ligands, and their interconnected linkers in PROTAC design, including their generation, structural optimization, and contribution to degradation efficiency and selectivity. Particularly, we analyzed the distinct preferences of various types of POI ligands (small molecule, nucleic acid, and peptide) toward specific targets. Furthermore, we emphasized the significant role of artificial intelligence technology in PROTAC design, including POI/E3 ligands discovery and linkers generation or optimization. We also summarized the applications and challenges of PROTACs in cancer therapy. Finally, we discussed the future development of PROTAC by combining multidisciplinary technologies and novel modalities for cancer therapy. Overall, this review aims to provide valuable insights for advancing PROTAC design strategies for cancer therapy.

As fundamental units of life activities, cells exhibit a high degree of structural refinement and functional specialization, forming the cornerstone of life complexity. Compartmentalization within cells is pivotal for maintaining the orderly progression of intracellular biochemical processes. Cellular compartments constitute the enclosed regions within the cytoplasm of all eukaryotic cells and are typically surrounded by a single or double layer of phospholipids, and include major organelles, such as the endoplasmic reticulum (ER) and mitochondria. Compartmentalization enables organelles to maintain distinct environments in terms of space, physics, and chemistry, thereby increasing their functionality. Human health is closely associated with cellular organelle homeostasis, and organelle dysfunction affects disease pathogenesis. In contrast to isolated cellular compartments, organelles are interdependent and communicate via membrane contact sites, with close membrane contact between the ER and mitochondria, forming mitochondria-associated ER membranes (MAMs), which are involved in multiple cellular functions and whose integrity and function are essential for cellular homeostasis, with dysfunction implicated in various diseases. Investigating MAMs structure, function, and disease-state alterations informs mechanisms and developing therapies. This article reviews the discovery, structure, function, and research progress of MAMs in human systemic diseases and cancer and explores their potential as therapeutic targets.

Artificial intelligence (AI) drives transformative changes in orthopedic surgery, steering it toward precision and personalization through intelligent applications in preoperative planning, intraoperative assistance, and postoperative rehabilitation/monitoring. Breakthroughs in deep learning, robotics, and multimodal data fusion have enabled AI to demonstrate significant advantages. Nonetheless, current applications face challenges such as limited real-time decision autonomy, fragmented medical data silos, standardization gaps restricting model generalization, and ethical/regulatory frameworks lagging behind technological advancements. Therefore, a critical analysis of the current status of AI and the acceleration of its clinical translation is urgently required. This study systematically reviews the core advancements, challenges, and future directions of AI in orthopedic surgery from technical, clinical, and ethical perspectives. It elaborates on the “perceptual-decisional-executional” intelligent closed loop formed by algorithmic innovation and hardware upgrades, summarizes AI applications across surgical continuum, analyzes ethical and regulatory challenges, and explores emerging trajectories. This review integrates the end-to-end applications of AI in orthopedics, illustrating its evolution. It introduces an “algorithm-hardware-ethics trinity” framework for technical translation, providing methodological guidance for interdisciplinary collaboration. Additionally, it evaluates the combined efficacy of diverse algorithms and devices through practical cases and details of future research frontiers, aiming to inform researchers of current landscapes and guide subsequent investigations.

Cellular senescence is a significant contributor to various age-related diseases. Tet methylcytosine dioxygenase 3 (TET3) is a pivotal regulator of epigenetic modifications, and this study aimed to elucidate its role in cellular senescence. The study utilized replication and paraquat (PQ)-induced senescent endothelial cells, as well as TET3 heterozygous, p53 heterozygous, and PQ-induced senescent mice as experimental models. Senescent endothelial cells were analyzed using hydromethylated DNA immunoprecipitation sequencing, β-galactosidase staining, real-time PCR, western blotting, immunofluorescence staining, dot blot, chromatin immunoprecipitation assay, and luciferase reporter assays. These analyses were conducted following TET3 knockdown and gene overexpression. TET3 is instrumental in the elevation of 5-hydroxymethylcytosine (5-hmC) levels in both replication and PQ-induced senescent endothelial cells, as well as in the cardiovascular systems of PQ-induced aging mice. TET3 significantly promoted cellular senescence in PQ-induced endothelial cells and mice. TET3 facilitates the upregulation of the Sp1 transcription factor (SP1) through 5-hmC modification, leading to a synergistic interaction between SP1 and ETS proto-oncogene 1 that further enhances p53 expression. Moreover, p53 not only promotes cellular senescence in vitro and in vivo but also reciprocally enhances TET3 and 5-hmC levels. These findings underscore the critical role of elevated TET3 and 5-hmC levels in cellular senescence.

Autoimmune diseases are a set of disorders in which the immune system attacks one's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. Affecting approximately 10% of the global population, these diseases impose significant health and economic burdens worldwide. The pathogenesis of autoimmune diseases is complex, involving not only genetic predisposition (e.g., human leukocyte antigen variants), environmental triggers (e.g., infections), and a dysregulated immune response but also various interacting components that contribute to the development of diverse clinical phenotypes. This review provides a comprehensive overview of common autoimmune diseases, covering their clinical manifestations, pathogenic mechanisms, and diagnostic approaches such as disease-specific autoantibodies. We also explore current therapeutic strategies, including commonly used broad-spectrum anti-inflammatory drugs, recent molecular-targeted therapies (e.g., Janus kinase inhibitors, monoclonal antibodies), and emerging cellular therapies such as chimeric antigen receptor T cells therapy and regulatory T-cell adoptive transfer. Incorporating knowledge from preclinical and clinical studies, this review synthesizes relevant information to inform about autoimmune diseases, bridge the gap from lab to clinic, and promote future advances through exploring precision medicine applications to meet clinical needs.

Persistent and intense endoplasmic reticulum (ER) stress is widely acknowledged as a hallmark of tumorigenesis. To restore ER homeostasis, cells activate the unfolded protein response (UPR), which is aberrantly regulated in cancer cells. This review provides an in-depth analysis of the mechanisms through which the UPR facilitates tumor progression. The UPR is activated by ER stress sensors such as inositol-requiring enzyme 1 (IRE1α), protein kinase R-like ER-resident kinase (PERK), and activating transcription factor 6 (ATF6). These sensors regulate cancer cell proliferation, immune evasion, metastasis, and drug resistance. We summarize the crosstalk between the UPR and multiple signaling pathways, including mTOR, MAPK, and NF-κB, which collectively promote tumor growth and metastasis. Additionally, we discuss the role of the UPR in modulating the tumor microenvironment to support angiogenesis and immune evasion. We also provide an overview of pharmacological agents targeting specific UPR pathways, such as GRP78 inhibitors, IRE1α inhibitors, PERK inhibitors, and ATF6 inhibitors, with the aim of developing more effective cancer therapies. This comprehensive review highlights the potential of targeting the UPR as a novel strategy for cancer treatment and underscores the need for further research to elucidate the complex interactions between the UPR and cancer progression.

The microbiota is pivotal for our health. It includes different phyla like Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia. The interaction between microbiota and immunity shares a bidirectional relationship. The microbiota helps to stimulate immunity development. The immunity influences microbial composition in turn. This interaction is critical for maintaining homeostasis, preventing pathogen invasion, and regulating the immune system. Furthermore, this symbiotic relationship is crucial for maintaining overall health and preventing various diseases. The microbiota–immune system contributes to immune system maturation, while the immune system selects for beneficial microbiota composition, thus enhancing our immunity. This review summarizes the molecular mechanisms and biological functions of the interaction between microbiota and immunity, offering solid evidence for the role of microbiota in immune regulation. Notably, the review categorizes microbiota according to phyla and explains disease associations, molecular effectors, and functional outcomes about the microbiota–immune system. We also introduced three core molecular mechanisms of the microbiota–immune systems. Moreover, we detail the progression from target discovery to clinical trial design for bacterial and immune-related diseases. Finally, we propose four therapeutic strategies for diseases.

The dysregulated accumulation of reactive oxygen species (ROS) and reactive nitrogen species disrupts redox homeostasis, triggering oxidative stress (OS) and driving pathophysiological changes across multiple organ systems. OS modulates critical signaling pathways, induces inflammation, impairs mitochondrial function, alters metabolic homeostasis, and dysregulates autophagy, contributing to disease progression. While prior research has largely focused on OS within single-organ diseases (e.g., neurodegenerative, cardiovascular, and oncological disorders), the systemic role of OS in pan-organ diseases and interorgan communication remains insufficiently explored. This review integrates multidisciplinary evidence to elucidate the biological functions of OS in cellular signaling, homeostasis, and cross-organ crosstalk. It systematically dissects OS-driven molecular mechanisms and pathophysiological networks across 10 major organ systems, including the nervous, cardiovascular, oncological, hepatic, and renal systems. Furthermore, it critically examines OS-related therapeutic targets, including antioxidant and ROS-generating enzymes, and explores synergistic redox-based therapeutic strategies. By moving beyond traditional single-organ paradigms, this review constructs a holistic framework to decode the systemic impact of OS, offering novel insights into disease mechanisms and therapeutic innovations. Ultimately, it lays the foundation for precision medicine approaches aimed at mitigating OS-driven diseases and improving multiorgan health outcomes.

Traditionally regarded as a metabolic waste product, lactic acid is now recognized as a crucial molecule in energy metabolism and signal transduction. It regulates various biological processes, including intracellular inflammation and immune responses. Notably, a novel epigenetic modification, lactylation, which is directly linked to lactic acid, was first identified by Professor Zhao Yingming's team in 2019. Lactylation influences gene expression and is associated with inflammation, cancer, and ischemic disease. Despite its potential significance, the precise mechanisms by which lactylation regulates gene expression remain unclear, and its implications in cardiovascular diseases are not yet fully understood. This review elucidates the relationship between lactic acid metabolism and cellular functions, highlighting its significant biological roles. This review provides a comprehensive analysis of the mechanistic role of lactylation in disease progression. It synthesizes research findings and emerging trends concerning lactic acid production and lactylation in the context of cardiovascular diseases. We explored potential therapeutic agents targeting lactylation and identified prospective treatment targets, offering novel insights into and directions for intervention strategies related to lactic acid production and lactylation. Ultimately, this review aims to pave the way for new therapeutic and research avenues in cardiovascular diseases.

Polycystic ovary syndrome (PCOS), a prevalent cause of female infertility, arises from complex interactions between genetic and environmental factors, with hyperandrogenism serving as a core pathological feature. While growing evidence links circadian disruptions to the development of hyperandrogenism in PCOS, the underlying mechanism remains unclear. In this study, we employed DNA methylation profiling and RNA sequencing of ovarian granulosa cells from rats exposed to 8-week darkness, and identified serpin family E member 1 (SERPINE1) as a key player. SERPINE1 was significantly hypomethylated and upregulated in the dark group, correlating with elevated androgen levels. Mechanistically, using CRISPR–dCas9-based targeted methylation, we found that CpG hypomethylation near the SERPINE1 transcription start site drove its overexpression. Functional assays revealed that SERPINE1 suppression activated the PI3K/AKT signaling pathway, thereby enhancing CYP19A1 expression and enzymatic activity to facilitate androgen conversion in vitro. Moreover, treatment with the SERPINE1 inhibitor tiplaxtinin alleviated both reproductive and metabolic abnormalities in rat models treated with either dehydroepiandrosterone or exposed to darkness. These findings highlight SERPINE1's role in circadian disruption-induced hyperandrogenism and its potential as a methylome-based diagnostic biomarker for PCOS. Pharmacological inhibition of SERPINE1 emerges as a promising therapeutic strategy for hyperandrogenic PCOS.

CVL218, a novel poly ADP-ribose polymerase (PARP1/2) inhibitor, has strong PARP1/2 selective inhibitory activity and high oral bioavailability. We aimed to assess the safety and tolerability of CVL218 in patients with pretreated advanced solid tumors. Patients in this phase I dose escalation trial received one dose of CVL218 (50, 100, 200, 350, 500, 600, 700, and 850 mg) twice a day. The safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), recommended dose, as well as antitumor activity of CVL218 were evaluated. A total of 26 patients were enrolled in this trial. The most common treatment-related adverse events were vomiting (76.9%), nausea (76.9%), diarrhea (38.5%), proteinuria (23.1%), and lipase increased (23.1%). DLTs occurred in three patients, one out of six in the 700 mg BID group, and two out of five in the 850 mg BID group, so the MTD was set to 700 mg BID. Overall, the disease control rate (DCR) was 70.8%, while the DCR of patients with high-level doses (≥700 mg BID) and recommended dose (700 mg BID) were both 100%. CVL218 was generally well tolerated and safe. It showed potential antitumor activity in patients treated with the recommended dose.

Original antigenic sin (OAS), or immune imprinting, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ancestral (WT) strain vaccine, or infection, has led to weakened neutralizing antibody response against Omicron variant like BA.2 and subvariant like XBB. This calls for the development of an innovative booster vaccine, or vaccination strategy, that will eliminate, or attenuate, OAS, thus, enhancing broad-neutralizing antibody (bnAb) response. Accordingly, we herein proposed a leveraged vaccination strategy to counter the OAS effect by controlling the antigenic distance of booster vaccine and increasing boost vaccination frequency. We found that prime with WT–RBD and boost with XBB–RBD resulted in significantly higher bnAb response against most Omicron subvariants tested than that after prime with WT–RBD and boost with BA.2–RBD because the antigenic distance between WT–RBD and XBB–RBD is much longer than that between WT–RBD and BA.2–RBD. An additional boost with XBB–RBD further enhanced bnAb response. These findings indicate that a leveraged vaccination approach based on antigenic distance could be effective in reducing OAS, thereby strengthening bnAb response against SARS-CoV-2 Omicron subvariants. As such, this vaccination strategy could be just as effective in combating other fast-evolving RNA viruses known for their high transmissibility and infectivity.

Myositis is a rare (<1%) but potentially severe immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), with a 40%–50% fatality rate. Its incidence and pathology in curative, neoadjuvant settings, particularly with chemoradiotherapy (CRT), remain poorly defined. Given the severity, stringent diagnostic and therapeutic approaches may be warranted in curative patients. In the CHINOREC trial, 50 rectal cancer (RC) patients receiving neoadjuvant CRT with ipilimumab (IPI) and nivolumab (NIVO) were prospectively monitored for myotoxicity biomarkers, including creatine kinase (CK) and cardiac troponins (cTnT, cTnI). Patients with CK and cTnT levels above the upper limit normal with or without overt clinical symptoms underwent muscle biopsy and guideline-adapted treatment (glucocorticoids, immunoglobulin, infliximab, plasma exchange). Six patients (12%) developed biopsy-confirmed myositis. Elevated cTnT, but not cTnI, distinguished skeletal from cardiac involvement, aligning with normal cardiac magnetic resonance imaging (CMR) findings. Immunohistochemistry showed a predominant CD8+ T cell infiltrate and patchy human leukocyte antigen (HLA) Class I upregulation. Despite myositis, all patients underwent successful tumor resection with normalized CK levels and no residual cardiac dysfunction. ICI-induced myositis may be more frequent in neoadjuvant-treated RC patients receiving CRT+ICI than in palliative settings. Comprehensive biomarker monitoring and early T cell-directed intervention are essential for mitigating life-threatening irAEs while preserving oncologic outcomes.

Mitochondrial dyshomeostasis provokes the onset of metabolic dysfunction-associated steatotic liver disease (MASLD) although its precise involvement in particular mitophagy in MASLD remains elusive. This work evaluated the role of casein kinase 2α (CK2α) and FUNDC1 in high-fat diet (HFD)-evoked MASLD. WT and CK2α deletion (CK2α^-/-) mice were subjected to low fat or HFD for 20 weeks. Global metabolism, AST, ALT, cholesterol, triglycerides, hepatic steatosis, fibrosis, inflammation, mitochondrial injury, mitophagy and ferroptosis were examined. Bioinformatics analysis enriched mitochondria-related pathways in MASLD. Hepatic CK2α and FUNDC1 were upregulated and downregulated, respectively, in MASLD patients and HFD-fed mice. HFD led to adiposity, hepatomegaly, hepatic steatosis, fibrosis, inflammation, ferroptosis, mitochondrial injury, elevated hepatic tissue Fe²⁺, FAS, CHREBP, SREBP1, PGC1α, PPARα, PPARγ, SCD1, PEPCK, G6Pase, and DGAT1 as well as downregulated FUNDC1, GPx4, SLC7A11 and NCOA4, the effects (except for NCOA4) were nullified by CK2α deletion. FUNDC1 deletion nullified CK2α deletion-evoked benefit on hepatic ferroptosis and lipid enzymes. In vitro study using palmitic acid indicated an obligatory role for CK2α, FUNDC1 and ferroptosis in hepatocyte steatosis. Collectively, our results demonstrated that CK2α activation by HFD serves as a trigger for mitochondrial damage, hepatic injury, and pathogenesis of MASLD through FUNDC1 disruption and ferroptosis.

Cancer progression is often driven by aberrant cell growth and genetic mutations, leading to metastasis. The transforming growth factor-beta (TGF-β) pathway, a key regulator of cellular growth and differentiation, exhibits dual roles in cancer by initially acting as a tumor suppressor and later promoting tumor progression and metastasis. Natural compounds, recognized for their diverse bioactivities and low toxicity, have shown potential in targeting cancer-related pathways, including TGF-β signaling. This review examines the therapeutic potential of natural products in modulating TGF-β signaling and their anticancer effects across various cancer types. We evaluated relevant preclinical and clinical studies assessing the impact of natural products on TGF-β modulation and cancer progression. Natural compounds from sources such as plants impact TGF-β signaling, influencing processes like cell proliferation, apoptosis, and angiogenesis. Key compounds reviewed include ginsenosides, halofuginone, and epigallocatechin gallate, demonstrating significant anticancer activity via TGF-β pathway modulation. These findings suggest natural products may serve as complementary therapies in cancer treatment by targeting TGF-β signaling, potentially improving patient outcomes. Continued research and clinical evaluation are necessary to integrate these compounds into conventional cancer therapies, aiming to offer safer, cost-effective options that enhance quality of life.

Long-term antiangiogenic therapy may be linked to medication-related osteonecrosis of the jaw (MRONJ), complicating surgical treatment due to impaired postoperative wound healing. However, the mechanisms underlying these healing difficulties remain unclear. This bidirectional cohort study explored the impact of antiangiogenic medications (AGM) in combination with antiresorptive medications (ARM) on oral mucosal microcirculation and its relationship with surgical outcomes in MRONJ patients. A total of 30 patients (15 using ARM and 15 using both ARM and AGM) and 15 healthy volunteers undergoing surgery were included. A handheld vital microscope (HVM) was utilized to assess oral mucosal microcirculation. The results showed that patients taking both AGM and ARM had reduced microvascular density and more stagnant microcirculation than patients taking ARM alone and healthy volunteers. Additionally, impaired microcirculation was also statistically linked to poorer surgical prognosis in MRONJ patients receiving AGM&ARM with lower microcirculation parameters. This study highlights the potential adverse effect of AGM on oral mucosal microcirculation, contributing to impaired wound healing after surgery in MRONJ patients. This study provides new evidence for the vascular mechanisms involved in healing difficulties in MRONJ and supports the hypothesis that AGM plays a detrimental role in oral surgical recovery.

The rapid global spread of antibiotic-resistant bacteria presents a growing public health crisis, threatening the efficacy of existing antimicrobial treatments. As traditional antibiotics become increasingly ineffective, alternative therapies such as bacteriophages and endolysins have gained renewed scientific and clinical interest. These biological agents, naturally derived from bacteriophage life cycles, exhibit potent and selective antibacterial activity, especially against multidrug-resistant pathogens. Despite decades of research, the clinical translation of phage and endolysin therapies remains limited due to regulatory, delivery, and stability challenges. This review provides a comprehensive overview of the mechanisms, advantages, and limitations of both bacteriophages and endolysins, including their structure, mode of action, and interaction with bacterial hosts. Particular attention is given to combination therapies, where synergistic effects have been observed–especially in biofilm-associated infections. We also explore the latest findings from preclinical studies, clinical trials, and compassionate-use cases, with an emphasis on genetically engineered and synthetic variants that enhance therapeutic potential. Furthermore, we discuss manufacturing challenges, regulatory barriers, and future directions such as personalized phage therapy and engineered endolysins. By synthesizing current knowledge, this review highlights the academic and translational significance of phage and endolysin-based approaches in combating antibiotic-resistant infections.

As a physicochemical mechanism, phase separation is a spatial and temporal regulator of specific molecules within a cell, and it provides a new perspective for understanding cellular pathophysiology. Phase separation is closely associated with multiple metabolic processes in the body, including the regulation of key metabolic enzymes and the physiology of mitochondria. Mitochondria also regulate multiple physiological functions through phase separation, including protecting healthy mitochondria and mRNAs in oocytes and regulating crosstalk between nuclear and mitochondrial. Importantly, abnormal phase separation in vivo is associated with the development of diseases, including cancer, neurodegenerative diseases, endocrine disorders, skeletal system diseases, and infectious diseases. This review summarizes the relationship between phase separation and metabolism under both physiological and pathological conditions, as well as the therapeutic potential of phase separation in the treatment of relevant diseases, aiming to explore the possibility of treating diseases by regulating phase separation.

Colorectal cancer (CRC) exhibits substantial intertumoral heterogeneity, largely attributable to multiple tumor stem-like cell populations, whose molecular identities and clinical significance remain incompletely defined. This study delineates tumor-intrinsic stem-like cell diversity and its prognostic implications through single-cell transcriptomic profiling of 171,906 tumor epithelial cells (n = 152), integrated with bulk transcriptomic (n = 1389) and genomic (n = 1077) datasets. Functional validation was conducted via in vitro assays and multiplex immunofluorescence. A previously unrecognized lysosome-associated transmembrane protein 4B-positive (LAPTM4B⁺) stem-like cell cluster was identified, distinct from the classical leucine-rich repeat-containing G-protein coupled receptor 5-positive (LGR5⁺) population. LAPTM4B⁺ cells exhibited MYC pathway activation and 8q chromosomal gains, with preferential enrichment in microsatellite-stable, POLE wild-type, and left-sided tumors. Stratification based on LAPTM4B⁺/LGR5⁺ stem-like cell ratios defined four CRC stem-like subtypes (CSS), with CSS2 (LAPTM4B⁺-dominant) associated with the poorest prognosis (HR = 2.31, p < 0.001). The combined expression of LAPTM4B and LGR5 demonstrated superior predictive power for CRC progression compared to either marker alone (AUC = 0.820 vs. 0.715/0.699), underscoring the synergistic influence of distinct stem-like cell populations on patient outcomes. These findings provide novel insights into CRC heterogeneity and cooperative interactions among diverse stem-like populations shaping disease outcomes.

Alteration in mitochondrial function within intestinal epithelial cells were closely related to inflammatory bowel disease (IBD) progression. Sulfide quinone oxidoreductase (SQOR), located in the inner mitochondria membrane, is a crucial enzyme in sulfide metabolism. Here, we observed that SQOR was downregulated during colitis. Intestinal epithelial cells specific knockout of SQOR (Sqor^CKO) mice were more susceptible to acute ulcerative colitis (UC) with lower hydrogen sulfide (H₂S) levels, and the absence of SQOR caused a breakdown of the epithelial barrier through disruption of the tight junction proteins. Furthermore, analysis of the mitochondrial morphology and functions revealed increased mitochondrial damage when SQOR deficiency. Mechanistically, it is observed that SQOR knockout increased lipid peroxidation, malondialdehyde (MDA) levels and ferroptosis. Further results demonstrated that SQOR may rely on inhibiting excessive mitochondrial division and promoting mitochondrial biogenesis to regulate reaction oxygen species (ROS) levels in intestinal epithelial cells. Treatment with ROS scavengers (NAC) showed significant reduced colonic inflammation symptoms observed in DSS-treated Sqor^CKO mice. Collectively, these findings demonstrate the protective role of SQOR in intestinal epithelial cells in maintaining mitochondrial homeostasis by regulating ROS and providing novel insight into UC.

HER2 expression is correlated with diminished efficacy of Bacillus Calmette–Guérin (BCG) instillation in high-risk non-muscle-invasive bladder cancer (HR-NMIBC). The development of effective intravesical treatments for HER2-expressing HR-NMIBC is of great urgency. In this single-arm phase I trial (ChiCTR2300073975), HER2-expressing HR-NMIBC patients received an induction course of weekly intravesical Disitamab vedotin (RC48) following a 3+3 design (60, 120, or 180 mg) for 6 weeks, followed by optional maintenance dose monthly for 11 sessions. The primary objective was to assess the safety and tolerability of intravesical RC48. The secondary objective was to determine the oncological outcomes. Between August 2023 and March 2024, nine patients were enrolled, and all completed the induction course without dose-limiting toxicities (DLTs) or grade ≥3 drug-related adverse events (AEs). The reported drug-related AEs included urinary tract infection (55.6%, 5/9), urinary frequency (11.1%, 1/9), and hematuria (11.1%, 1/9). The 6-month and 12-month recurrence-free survival (RFS) rates were 100% (8/8) and 87.5% (7/8), respectively, whereas the progression-free survival (PFS) rates were 100% (8/8) and 100% (8/8). Taken together, these findings indicate that intravesical RC48 was well tolerated and showed preliminary efficacy in HER2-expressing HR-NMIBC. The maximum tolerated dose was not reached, and further dose exploration is ongoing (NCT06378242).

Cancer-associated fibroblasts (CAFs) are functionally diverse stromal regulators that orchestrate tumor progression, metastasis, and therapy resistance through dynamic crosstalk within the tumor microenvironment (TME). Recent advances in single-cell multiomics and spatial transcriptomics have identified conserved CAF subtypes with distinct molecular signatures, spatial distributions, and context-dependent roles, highlighting their dual capacity to promote immunosuppression or restrain tumor growth. However, therapeutic strategies struggle to reconcile this functional duality, hindering clinical translation. This review systematically categorizes CAF subtypes by origin, biomarkers, and TME-specific functions, focusing on their roles in chemoresistance, maintenance of stemness, and formation of immunosuppressive niches. We evaluate emerging targeting approaches, including selective depletion of tumor-promoting subsets (e.g., fibroblast activation protein+ CAFs), epigenetic reprogramming toward antitumor phenotypes, and inhibition of CXCL12/CXCR4 or transforming growth factor-beta signaling pathways. Spatial multiomics-driven combinatorial therapies, such as the synergistic use of CAFs and immune checkpoint inhibitors, are highlighted as strategies to overcome microenvironment-driven resistance. By integrating CAF biology with translational advances, this work provides a roadmap for developing subtype-specific biomarkers and precision stromal therapies, directly informing efforts to disrupt tumor-stroma coevolution. Key concepts include spatial transcriptomics, stromal reprogramming, and tumor-stroma coevolution, offering actionable insights for both mechanistic research and clinical innovation.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by T-cell-mediated B-cell hyperactivity and cytokine production, clinically manifesting, dry mouth and eyes, accompanied by pain and fatigue. The disease may progress from asymptomatic glandular involvement to systemic manifestations or even lymphoma. The pathogenesis of SS is intricate, involving a multifaceted interplay of genetic, environmental, and immunological factors. There is still uncertainty regarding the effectiveness of SS-targeted treatments, due to the significant diversity in disease phenotypes and potentially varying responses to immunomodulatory therapies, stringent enrollment criteria and adoption of outcome metrics in clinical trials may partially explain the failure of many trials to achieve their primary outcomes. Despite the current lack of effective treatments, recent advancements have been made in epidemiology, the development of classification criteria, and the establishment of systems for assessing disease activity. Notably, enhanced insights into the pathogenesis have paved the way for the potential development of targeted therapies. This review aims to systematically synthesize the latest research advancements in the epidemiological characteristics, diagnostic criteria, molecular mechanisms, and clinical manifestations of SS, thereby providing a scientific foundation for the development of future therapeutic strategies.

Phosphate is an important element in biological processes, particularly in the formation and metabolism of mineralized tissues such as bones and teeth. The imbalance of phosphate is also closely related with pathological mineralization. Restoring the phosphate homeostasis is an attractive target to treat diseases related with pathological mineralization. However, the inherent consistency of phosphate's role in both physiological and pathological mineralization has been overlooked in previous investigations. This review highlights the multifaceted role of phosphate as a building block, and as a signaling molecule that regulates the activity of mineralizing cells in both physiological and pathological mineralization. This direct and indirect role of phosphate acts as a bridge between physiological and pathological mineralization. The review also discusses the genetic mutations associated with phosphate-related mineralization disorders, emphasizing the need for further genetic and molecular research to uncover additional factors and mechanisms. Future research directions proposed include enhancing our understanding of phosphate sensing and regulation mechanisms, investigating new therapeutic agents, and developing reliable biomarkers for early diagnosis and treatment of phosphate-related mineralization disorders. By advancing our knowledge in these areas, we can improve the prevention, diagnosis, and treatment of phosphate-related mineralization disorders to enhance patient outcomes and their quality of life.