Forkhead box P3 (FOXP3), the master regulator of regulatory T cells (Tregs), is aberrantly expressed in tumor cells, including lung cancer. Alternative splicing generates multiple isoforms, among which the full-length FOXP3 (FOXP3FL) and exon 3-deleted variant (FOXP3Δ3) are predominant. We identified FOXP3Δ3 as the major isoform in non-small cell lung cancer (NSCLC) tumor cells. FOXP3Δ3 expression was elevated in tumor tissues and correlated with larger tumor size and advanced T stage. Functional assays showed that tumoral FOXP3Δ3 enhanced proliferation, invasion, migration, stemness, and apoptosis resistance in NSCLC cells, exerting stronger effects than FOXP3FL. Knockdown of FOXP3Δ3 in NSCLC cells suppressed tumor growth in nude mice, confirming its oncogenic activity in vivo. Mechanistically, FOXP3Δ3 upregulated phosphorylated STAT3 and mesenchymal markers (N-cadherin, Vimentin, Snail), while reducing epithelial marker E-cadherin compared with FOXP3FL. Coimmunoprecipitation indicated these differences may arise from distinct STAT3 binding affinities. Additionally, FOXP3Δ3 decreased cisplatin-induced apoptosis, suggesting a role in chemoresistance. In summary, FOXP3Δ3 is the predominant oncogenic FOXP3 isoform in NSCLC tumor cells, promoting tumor cell progression and therapy resistance through STAT3 signaling. These findings highlight FOXP3Δ3 as a potential therapeutic target.
Connexins, a family of transmembrane proteins, are essential for intercellular communication in the mammalian central nervous system, particularly through their assembly into gap junction channels. This review explores the central role of connexin-mediated signalling in hypothalamic regulation of nutrient metabolism and energy homeostasis, together with the function of connexins in peripheral metabolic organs. Focusing on connexins Cx43 and Cx30, we discuss their specific expression within hypothalamic neuroglial populations, including astrocytes and tanycytes, and their involvement in glucose sensing, metabolic signalling, and neuroendocrine regulation. Functional studies demonstrate that hypothalamic Cx43 is dynamically regulated by metabolic status, while its knockdown impairs glucose-stimulated insulin secretion and systemic energy balance. Tanycytes, interconnected into a Cx43-dependent network, play a critical role in relaying metabolic cues from cerebrospinal fluid and blood to hypothalamic neurons, thereby orchestrating adaptive responses to glycaemic changes. The review further details how the disruption of connexin-mediated coupling in tanycytes leads to impaired glucose sensing, altered neuronal activity, and systemic metabolic disorders. Beyond the hypothalamus, this review also summarizes how connexins in peripheral metabolic organs contribute to metabolic homeostasis, inflammatory regulation, and disease progression. Collectively, these discoveries highlight the fundamental importance of connexins in integrating metabolic signals and maintaining systemic homeostasis.
Premature ovarian insufficiency (POI) causes early loss of ovarian function, though its underlying metabolic-epigenetic mechanisms remain unclear. Using ovarian tissues from POI patients and a cisplatin-induced mouse model, we investigated the role of the NAD+-dependent deacetylase Sirtuin 1 (SIRT1) in granulosa cells. We found that SIRT1 expression was markedly downregulated in POI, correlating with hyperacetylation of the glycolytic enzyme pyruvate kinase M2 (PKM2) and pathogenic lactate accumulation. Restoring SIRT1 activity via intra-ovarian AAV-SIRT1 delivery or systemic administration of nicotinamide mononucleotide (NMN) reversed these phenotypes. This intervention improved follicular development, reduced granulosa cell apoptosis, and normalized serum anti-Müllerian hormone and follicle-stimulating hormone levels. Mechanistically, SIRT1 directly interacts with and deacetylates PKM2, suppressing its activity and limiting lactate production. Our work defines a critical SIRT1-PKM2-lactate metabolic axis that maintains ovarian homeostasis. Targeting this axis via NAD+-boosting interventions, such as NMN, presents a promising novel therapeutic strategy for POI.
Abstract Bile acids (BAs) have evolved from their classical definition as digestive surfactants to be recognized as potent endocrine signaling molecules that orchestrate systemic metabolism. Through activation of nuclear receptors such as farnesoid X receptor (FXR) and membrane receptors such as G protein-coupled BA receptor 1 (GPBAR1/TGR5), BAs regulate glucose, lipid, immune, and energy homeostasis. Aging reshapes BA synthesis, enterohepatic circulation, hydrophobicity, microbial biotransformation, and receptor responsiveness, thereby linking BA metabolism to hepatic senescence, inflammaging, and age-associated liver vulnerability. In turn, dysregulated BA signaling can amplify mitochondrial stress, endoplasmic reticulum stress, impaired autophagy, immune dysfunction, and senescence-associated secretory phenotypes, suggesting a bidirectional relationship between BA remodeling and aging progression. This review critically examines the role of BAs as hormone-like mediators within the aging liver microenvironment, summarizes major BA species and receptor preferences, integrates gut microbiota–BA crosstalk, and evaluates the therapeutic potential and caveats of targeting the BA–FXR–TGR5 axis in aging-related liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), autoimmune liver diseases (AILDs), chronic hepatitis B (CHB), and hepatocellular carcinoma (HCC).
A growing body of evidence suggests that aging is not simply the accumulation of damage, but a systemic progression of increasing entropy across biological scales. Synthesizing concepts from thermodynamics and information theory, we outline a tentative three-stage entropy model of the lifespan: order-building development, homeostatic adulthood, and disorder-dominant aging. Within this model, we attempt to reframe the established hallmarks of aging as interconnected nodes in an entropy-centered network and detail the multiscale manifestations of disorder from molecules to systems. To quantify this trajectory, we introduce a Multiscale Entropic Aging Index (MEAI) as a proof-of-concept conceptual framework, designed to integrate measurements of disorder across biological levels. This framework seeks to offer a potential unifying, quantitative language for aging research and suggests that entropy reduction could serve as a testable mechanism underlying interventions, laying a principled foundation for the future development of biomarkers and rejuvenative strategies.
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations, found in 25%-30% of acute myeloid leukemia (AML) patients, cause poor prognosis and resistance to FLT3 tyrosine kinase inhibitors (TKIs). We show that APG-115 selectively kills FLT3-ITD cells by activating p53. This critically upregulates TRIM22 (Tripartite motif-containing protein 22), an essential E3 ubiquitin ligase that directly binds FLT3-ITD, promotes its polyubiquitination, and induces its proteasomal degradation. This TRIM22-mediated mechanism offers a novel strategy to overcome intrinsic and acquired TKI resistance. Unlike inhibitors such as AC220, which suppress FLT3 signaling but downregulate p53, APG-115 restores p53 function and induces TRIM22, enabling potent synergy with FLT3 inhibitors. TRIM22 is essential for APG-115's suppression of leukemia stem cells, inducing cell cycle arrest, myeloid differentiation, and reduced clonogenic potential. The combination of APG-115 and AC220 significantly enhances apoptosis in FLT3-ITD AML models and primary cells, while sparing normal cells. It shows robust efficacy in preclinical xenograft models, reducing tumor burden and extending survival. This work establishes targeting the p53/TRIM22 axis, reliant on TRIM22's unique activity against FLT3-ITD, as a highly promising therapeutic approach for FLT3-ITD AML, including resistant disease.
Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed "tauopathy", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the "atypical" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.
Aortic dissection (AD) is a fatal emergency which lacks effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis, and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8, in human aortic smooth muscle cell (HASMC) ferroptosis and β-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by an increase in cell viability, reduction in cell injury/death, and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.
Integrated genomic evidence on shared genetic architecture between obesity and psychiatric disorders remains limited. This work utilized multi-level genomic analytic approaches to identify pleiotropic loci, variants, and genes between 14 adiposity traits and 7 psychiatric disorders, including genetic correlation and bidirectional causality as well as gene expression, functional pathway, and druggability, using genome-wide association study data from up to 806,834 individuals of European descent. Based on 67 genetically correlated trait pairs established between the two groups, we identified 17 causal shared genes across 26 tissues, which were enriched in neurodevelopment, neuronal function, cellular transport, and developmental biology. Of these, NEGR1, CTNNB1, TAOK2, and RTN4RL1 were located in the druggable genome, and CTNNB1 and NT5C2 were clinically actionable. Mendelian randomization further supported extensive bidirectional causal associations. These findings provide robust evidence for a shared genetic etiology between adiposity and psychiatric disorders, underscoring mechanistic links and prioritizing actionable targets for comorbidity intervention.
Eosinophilic esophagitis (EoE) is a chronic immune disease requiring repeated endoscopies for diagnosis and monitoring in children. Saliva represents a promising non-invasive biofluid, and volatile organic compounds (VOCs) may indicate disease presence and activity. This study aimed to examine the VOCs profile in saliva samples from children with EoE and to compare it with other gastrointestinal (GI) conditions and healthy controls. Thirty-five samples from children with EoE (including 13 active and 22 non-active cases), 19 from children with other GI conditions, and 46 from healthy controls were analyzed. Gas chromatography-ion mobility spectrometry (GC-IMS) identified 63 distinct VOC signal areas. The abundance of 16 of them was found significantly different (P < 0.01) in EoE vs. controls, EoE vs. other GI conditions, and active vs. non-active EoE. Among them, cis-3-hexen-1-ol and 2-phenylethanol show a ubiquitous capability to discriminate EoE against different populations. Linear discriminant analysis (LDA) of the panel of 16 VOCs achieved 83.3% accuracy in classifying EoE vs. healthy controls, 81.2% accuracy in distinguishing EoE from GI controls, and 80.0% accuracy in classifying active vs. non-active EoE. Salivary VOC profiling enables accurate discrimination of pediatric EoE from controls and stratification by disease activity. This non-invasive approach holds promise as a diagnostic and monitoring tool in clinical practice, especially in children.
The human placenta sustains pregnancy through intricate trophoblast lineage dynamics that are critical for fetal development and pregnancy success. While studies on protein-coding genes (PCGs) have advanced our understanding of placental biology, the regulatory roles of noncoding RNAs, particularly long noncoding RNAs (lncRNAs), in trophoblast lineage specification and function remain poorly understood. Here, we profile single-cell lncRNA dynamics across human placental development, revealing distinct cell-type- and gestational stage-specific expression profiles. Integrated analysis revealed that lncRNAs modulate histone modification levels at the regulatory regions of target genes via cis-action, thereby regulating the expression of key genes essential for trophoblast differentiation. Functional studies by using in vivo and in vitro models fully identify ECEL1P2-ALPP, SEMA3B-AS1-SEMA3B, and MYCNUT/MYCNOS-MYCN as pivotal regulatory axes driving cytotrophoblast self-renewal, syncytiotrophoblast fusion, and epithelial-mesenchymal transition, respectively, which are essential for trophoblast identity and function. Notably, dysregulation of lncRNA-PCG pairs in pathological pregnancies underscores the clinical relevance of these noncoding networks. Together, our findings uncover an unappreciated layer of lineage-specific noncoding regulation, providing mechanistic insight and potential biomarkers for placental development and associated disorders.
NME1 is a key metastasis suppressor whose activity depends on histidine phosphorylation, yet the biological significance of this modification remains poorly understood. Here, we reveal a previously unrecognized role for NME1 in regulating the Hippo pathway. Using PhastID-based proximity labeling combined with functional assays, we demonstrate that NME1 modulates CDC42 activity via ARHGAP17, a GTPase-activating protein, thereby influencing cytoskeletal organization and Hippo activation. Loss of NME1 reduced YAP phosphorylation and promoted its nuclear localization, indicating suppression of Hippo signaling. These findings define a histidine phosphorylation-dependent NME1-ARHGAP17-CDC42-cytoskeleton axis that controls the Hippo pathway, providing new insights into the functional repertoire of NME1 in cancer and development.
Spinal cord injury (SCI) is a devastating condition affecting the central nervous system, often leading to persistent neurological dysfunction. While mesenchymal progenitor cells (MPCs) hold considerable promise for treating various disorders, their application in SCI repair remains hampered by challenges such as poor efficacy and safety concerns. In this study, we developed genetically engineered human MPCs with enhanced resistance to senescence and stress-termed senescence- and stress-resistant cells (SRCs)-and systematically evaluated their therapeutic potential and mechanisms in SCI repair. Intramedullary implantation of SRCs improved functional recovery after SCI. Mechanistically, SRCs exerted therapeutic effects through a dual approach: by mitigating neuronal and axonal loss while stimulating endogenous neuroregeneration, and by suppressing neuroinflammation while modulating astrocyte distribution to restrict lesion expansion. Importantly, we identified exosomes derived from SRCs as key mediators of these reparative effects. Our findings provide comprehensive insights into the therapeutic role of engineered SRCs in SCI repair, delineating both direct cellular and exosome-mediated mechanisms, thus providing experimental support for future clinical translation.
