Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master transcriptional coactivator responsible for regulating cellular energy metabolism and mitochondrial biogenesis across high-energy tissues such as the heart, skeletal muscle, and brown adipose tissue. To orchestrate its regulatory functions, PGC-1α interacts with a diverse array of transcription factors such as peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs), which is facilitated by its dynamic three-dimensional structure, the presence of distinct functional domains, and the ability to be modulated via post-translational modifications. This review examines the protein's interactions with key nuclear receptors and the biological consequences of these complexes, including the regulation of thermogenesis, gluconeogenesis, and fatty acid oxidation. Furthermore, we discuss the extensive post-translational modifications-including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination-that tightly regulate PGC-1α stability and coactivation efficiency. Finally, this review highlights recent progress in the identification of small molecule modulators, such as the activator ZLN005 and the inhibitor SR18292, evaluating their physiological outcomes and potential as therapeutic agents for metabolic disorders and cancer, while addressing the challenges posed by the protein's structural disorder in drug discovery.
Morin (2',3,4',5,7-pentahydroxyflavone) is a polyphenolic dietary flavonoid found naturally in foods and has demonstrated anticancer effects in multiple preclinical models. This narrative review presents a comprehensive pharmacological analysis of morin's capacity to modulate apoptosis and autophagy, which are convergent pathways of programmed cell death (PCD) in both solid and hematological malignancies. Morin has been reported to influence intracellular reactive oxygen species (ROS) levels and disrupt the mitochondrial membrane potential (ΔΨm), thereby affecting the AMPK-mTOR-ULK1-Beclin-1 autophagic pathway. This review synthesizes preclinical data obtained from in vitro cancer cell line models, in vivo xenograft and chemical-induced tumor systems, and hypothesis-generating in silico molecular docking and network pharmacology studies. The significant crosstalk between apoptosis and autophagy appears to involve the Bcl-2/Beclin-1 pathway, cleavage of autophagy-related proteins by caspases, and shared redox stress. Mechanistic interpretation should be used with caution, as several studies have used associative molecular end points, and the accumulation of LC3-II does not equate to complete autophagic flux. Novel nanoformulation-based drug delivery strategies, the potential of chemo-sensitization in drug-resistant tumor models, and available preclinical safety and toxicology data are examined in the context of the pharmacokinetic limitations of morin, such as poor oral bioavailability, low aqueous solubility, intestinal metabolism, P-glycoprotein efflux, and limited clinical pharmacokinetic validation. Pharmacological studies suggest that morin may be classified as a multi-target phytopharmacological agent. However, more rigorous studies are required for target validation, including autophagy flux assays, clinically relevant tumor models, and pharmacokinetic optimization, before it can be translated into a therapeutic application.
Antigen escape and intratumoral heterogeneity remain major barriers to durable responses in chimeric antigen receptor (CAR)-based cancer immunotherapies. While single-antigen CAR-T cell therapies have achieved notable success in hematologic malignancies, relapse driven by antigen loss, lineage plasticity, and tumor evolution remains common, and efficacy in solid tumors is limited. Similar antigen-dependent limitations are also observed in other targeted immunotherapies, including bispecific antibodies, underscoring the broader challenge of achieving durable immune control. To address these challenges, bispecific and combinatorial CAR strategies have emerged to broaden antigen coverage, enhance tumor selectivity, and reduce immune evasion. This review examines the biological mechanisms underlying antigen escape and critically evaluates dual-targeting CAR architectures, including tandem CARs, dual-CAR systems, logic-gated designs, and inhibitory CARs. We distinguish between mechanistic rationale and clinically validated benefit, highlighting the heterogeneity of outcomes across studies and the limited evidence supporting consistent superiority over optimized monospecific approaches. We summarize preclinical and clinical evidence supporting bispecific CAR-T strategies, particularly in B-cell malignancies, while discussing challenges related to toxicity, manufacturing complexity, and translational scalability. We further evaluate CAR-engineered natural killer (CAR-NK) cells as a complementary platform. Their innate cytotoxicity, favorable safety profile, and compatibility with allogeneic manufacturing offer important translational advantages, although limitations in persistence, tumor infiltration, and clinical validation remain. Finally, we position CAR-based therapies within the evolving immunotherapy landscape, emphasizing therapeutic sequencing, combination strategies, potential cross-resistance, and the need to align CAR design and platform selection with tumor-specific patterns of antigen expression and immune escape.
Preeclampsia (PE), a hypertensive disorder unique to pregnancy, is linked to impaired trophoblast function. DEAD-box helicase 39B (DDX39B) plays key roles in embryonic development. This study investigated its role in regulating trophoblast biology during PE progression. We conducted functional assays using CCK-8, clone formation, EdU, Transwell, Wound healing and TUNEL in the HTR-8/SVneo trophoblast cells. The interaction between Wilms tumor 1-associating protein (WTAP) and DDX39B was analyzed by Co-IP assay. RIP assay or RNA pull down were used to assess the association between the ELAV-like RNA-binding protein 1 (ELAVL1)/WTAP and L-lactate dehydrogenase A (LDHA) mRNA. Additionally, MeRIP assay was employed to evaluate m6A levels on LDHA transcripts. Overexpression of DDX39B promoted the proliferation and migration of trophoblast cells and suppressed cells apoptosis, while DDX39B knockdown had the opposite result. In addition, WTAP knockdown reversed the promoting effects of DDX39B overexpression on trophoblast proliferation and migration. Mechanistically, DDX39B promoted post-translational stabilization of WTAP by directly interacting with WTAP protein. WTAP enhanced the m6A methylation of LDHA mRNA by recruiting ELAVL1. As expected, LDHA knockdown abrogated the pro-proliferative and anti-apoptotic effects of WTAP overexpression on trophoblasts. Our findings established a novel DDX39B/WTAP/m6A/LDHA regulatory axis, wherein DDX39B acted as an RNA-binding protein to stabilize WTAP, enhancing LDHA expression and promoting trophoblast proliferation, migration, and survival. Dysregulation of this pathway might contribute to PE pathogenesis, offering new avenues for targeted therapies.
Breast and cervical cancers remain significant causes of cancer-related deaths in women, necessitating the development of effective treatments. This study investigated the repositioning potential of procaterol as a chemosensitizer to increase the efficacy of cisplatin in HeLa and MCF-7 cells. On its own, procaterol showed limited cytotoxicity; however, it significantly inhibited cell viability when combined with low doses of cisplatin. Both colony formation and cell proliferation studies showed a strong inhibition of cell growth, especially in HeLa cells. Similarly, wound-healing studies showed greater inhibition of cell migration in the presence of both drugs than with either drug alone. Live/dead assays and elevated TNF-α (tumour necrosis factor-alpha) expression confirmed apoptosis. The increased generation of reactive oxygen species suggested that HeLa cells are under oxidative stress. Flow cytometric analyses showed that procaterol induced G0/G1 arrest, cisplatin induced G2/M arrest, and the combination induced both arrests while significantly decreasing S-phase populations. Procaterol sensitized cisplatin by increasing apoptosis and oxidative stress and inducing cell cycle arrest. As an FDA-approved compound, it can be used as a cost-effective adjuvant for treating breast and cervical cancer. Additional in vivo verification and clinical trials are required to establish the translational value of this new combination for the treatment of cervical and breast cancer.
The dynamics of surface carriers in conventional n-type semiconductors are generally restricted by the energy band bending at their interfaces, thereby severely limiting the extraction of photoelectrons for cathodic bioassays. Herein, we reported a nonconventional cathodic photoelectrochemical (PEC) immunoassay, utilizing an Ag-decorated Gd-doped BiFeO3 (Ag/BGFO) Schottky junction for fundamentally overriding the n-type depletion limitations. Despite its typical n-type nature confirmed by Mott-Schottky analysis, the BGFO photoelectrode generates a robust cathodic photocurrent of 23.5 μA at 0 V, which is more than four times higher than pure BFO. This counterintuitive phenomenon is governed by the powerful spontaneous depolarization field (Edp) of the ferroelectric BGFO, which forcefully pumps photoelectrons to the surface, overriding the conventional depletion layer. Subsequently, the upward-bent Ag/BGFO Schottky barrier acts as a unidirectional valve, efficiently extracting these electrons into the Ag electron sinks while strictly preventing interfacial backflow. Leveraging this exceptionally electron-rich cathodic platform, a split-type PEC immunosensor was constructed for α-fetoprotein (AFP) detection. By spatially isolating the target-triggered enzymatic generation of H2O2 from the photoelectric interface, the sensor thoroughly eliminates biofouling, achieving an ultralow limit of detection of 2.46 pg/mL and a remarkable 90-day storage stability (>97% retention). Furthermore, clinical validation using 50 human serum specimens demonstrated an excellent linear correlation (R2 = 0.9986) with the gold-standard ELISA. This work not only provides profound physical insights into ferroelectric-modulated charge dynamics but also establishes a highly robust paradigm for translational clinical diagnostics.
Self-amplifying RNA (saRNA) derived from alphavirus replicons enables robust intracellular RNA amplification and high-level protein expression at substantially lower doses than nonreplicating messenger RNA (mRNA) platforms. Venezuelan equine encephalitis virus (VEEV)-based replicons lacking the viral structural genes are among the most extensively characterized saRNA backbones, combining efficient cytoplasmic replication with a favorable safety profile. However, incorporating chemical nucleoside modifications such as N1-methylpseudouridine (m1ψ), now standard in conventional mRNA workflows, can directly impact replicase activity and hinder RNA amplification, necessitating backbone-specific optimization. Recent studies have shown that incorporation of 5-methylcytidine (m5C) preserves VEEV saRNA replication while reducing innate immune activation and improving expression durability. In an independent study, phosphatase treatment to remove residual 5'-triphosphates was shown to enhance saRNA functionality. Building on these findings, here we describe a streamlined protocol for generating m5C-modified VEEV-based saRNA using a single-step in vitro transcription (IVT) strategy. This protocol utilizes PCR-generated DNA templates with an encoded poly(A) tail, CleanCap AU for co-transcriptional capping, and post-transcriptional phosphatase treatment to minimize immunostimulatory RNA species. Finally, the RNA was purified using the phenol-chloroform-isoamyl alcohol method and functionally evaluated by transfection into HEK293T cells. This protocol provides a reproducible framework for producing capped, tailed, and chemically modified saRNA suitable for downstream functional and translational studies. © 2026 Wiley Periodicals LLC. Basic Protocol 1: IVT and purification of saRNA with modified nucleotides Basic Protocol 2: Functional assessment of IVT-generated saRNA in HEK293T Cells.
To evaluate whether cumin (Cuminum cyminum) oil attenuates nandrolone decanoate (ND)-induced hepatic alterations in rats. Eighty male Sprague-Dawley rats were randomized into six groups: control, cumin oil alone, ND low dose (10 mg/kg/week), ND high dose (20 mg/kg/week), ND low dose + cumin oil, and ND high dose + cumin oil. Cumin oil was administered orally at 400 mg/kg/day for 4 weeks. Outcomes included relative liver weight index, serum ALT/AST, total bilirubin, lipid profile, and blinded histopathology. Both ND doses increased ALT/AST and bilirubin levels and worsened the lipid profile compared with controls, with more pronounced and significant alterations in the high-dose ND group. Co-administration of cumin oil attenuated ND-associated elevations in liver enzymes and bilirubin, improved lipid parameters, and was associated with reduced histological damage compared with ND alone. Interestingly, cumin oil alone increased ALT/AST and lipid parameters compared with controls, although liver architecture remained unremarkable on H&E. In this rat model, cumin oil co-administration partially attenuated ND-induced hepatic biochemical, lipid, and histological alterations. However, cumin oil alone increased ALT/AST and lipid parameters despite unremarkable H&E morphology. Therefore, the present findings should be interpreted as evidence of context-dependent attenuation during ND exposure, not as proof of an independent hepatoprotective or lipid-lowering effect of cumin oil in healthy rats. Dose-ranging, safety evaluation, batch-specific chemical profiling, preparation standardization, and mechanistic studies incorporating antioxidant/oxidative stress markers such as MDA, GSH, SOD, CAT, GPx, and molecular endpoints are needed to clarify pathways and translational relevance.
Ebola virus disease (EVD) is a severe and often fatal illness characterized by aggressive viral replication, dysregulated immunity, and multi-organ dysfunction. Emerging evidence demonstrates that microRNAs (miRNAs), both host-derived and virus-encoded, play essential regulatory roles throughout the course of Ebola virus (EBOV) infection. Host miRNAs are widely dysregulated across different tissues and cell types during infection and contribute to antiviral defense, viral persistence, immune suppression, endothelial dysfunction, and hemorrhagic pathology. In parallel, EBOV generates its own miRNA-like molecules that target key host signaling pathways, including nuclear transport, interferon responses, apoptosis regulation, and inflammatory cascades. These dual layers of miRNA crosstalk shape infection outcomes by modulating viral replication, immune evasion, cellular adhesion, and vascular leakage. Additionally, several host and viral miRNAs show strong potential as diagnostic and prognostic biomarkers, and recent work suggests that therapeutic modulation through miRNA mimics or inhibitors may offer new antiviral strategies. This review synthesizes current evidence on miRNA interactions during EBOV infection and outlines their implications for disease pathogenesis, clinical outcomes, and translational applications.
Pulmonary arterial hypertension (PAH) is increasingly recognized as a metabolically dysregulated and inflammatory vascular disease rather than a purely haemodynamic disorder. Among emerging metabolic pathways, the bile acid-oxysterol axis has gained attention as a potential link between sterol imbalance, endothelial dysfunction, and pulmonary vascular remodeling. This narrative review examines current evidence linking selected bile acid and oxysterol species to PAH phenotypes and discusses their potential mechanistic and translational implications. Human lung tissue studies, circulating metabolomics, and experimental models suggest that selected bile acid intermediates and oxysterol species may carry biological information beyond nonspecific disease severity, although their effects are molecule-specific, receptor-specific, and context-dependent rather than uniform across the entire metabolite class. In particular, recent work implicates disturbed lysosomal sterol trafficking and impaired endothelial lysosomal acidification, including NCOA7-related mechanisms, in generating pro-inflammatory sterol signatures that promote endothelial immunoactivation and worsen experimental PAH. At the same time, the biological origin and interpretation of these metabolites are likely heterogeneous, involving lung-intrinsic sterol remodeling, systemic gut-liver signals, and potential confounding from right-heart failure or congestive hepatopathy. We argue that the bile acid-oxysterol axis should not be viewed as uniformly causal or purely biomarker-like across all patients, but rather as a compartment- and endotype-dependent framework whose interpretation depends on the level of evidence considered. This framework has important implications for biomarker development, therapeutic targeting, and precision trial design, and identifies sterol trafficking and lysosomal homeostasis as promising areas for future investigation.
Explainable Artificial Intelligence (XAI) is gaining popularity in early diagnosis and monitoring of dementia. Herein, we recommend the incorporation of the National Institute of Mental Health's Research Domain Criteria (NIMH-RDoC) framework with XAI-informed diagnostic protocols to help establish diagnosis at early stages of Alzheimer's disease (AD). RDoC has a dimensional structure that extends across units of analysis from genes and molecules to circuits, physiology, behavior, and introspection. By restructuring diverse features as inputs including apolipoprotein E (APOE) genotype, amyloid and tau biomarkers, computational neuroimaging-informed cortical atrophy, Positron Emission Tomography (PET) hypometabolism, quantitative electroencephalography (qEEG) rhythms, cognitive tests, and digital behavioral markers), onto RDoC units provides more insightful and inclusive models. In this context, data-driven approaches such as XAI can achieve not only increased interpretability but also enhance their mechanistic validity. Such an innovative approach places data-driven model outputs within neurobiologically based domains such as Cognitive Systems, Negative Valence, and Arousal/Regulatory Systems. Our synthesis suggests that a 'converging RDoC and XAI' approach may help bolster the coherence of AD biomarkers, promote model exploration in clinical decision-making. This approach is also expected to provide a strategic roadmap for translational neuroscience and personalized medicine. Another major aim of this study is to critically analyze current XAI approaches used in dementia research, particularly the diagnostic and prognostic aspects. By explicitly grounding explanations in RDoC cognitive domains and paradigms, the framework also aims to make model outputs meaningful in terms of specific mental functions (e.g., episodic memory, cognitive control), thereby supporting neuropsychologically-informed diagnosis, categorization, and communication with patients and caregivers.
Parkinson's Disease (PD) represents the second most prevalent neurodegenerative condition which leads to the progressive destruction of dopaminergic neurons in the substantia nigra through oxidative stress mechanisms. The research evaluated Gallic Acid (GA) as a natural polyphenol with proven antioxidant properties for its ability to protect cells from 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity in SH-SY5Y dopaminergic cell models. The research used SH-SY5Y cells which received 1 mM MPP⁺ treatment alongside different GA concentrations (25, 50 and 100 µM) for 24 and 48 h. The CCK-8 assay measured cell viability while flow cytometry evaluated apoptosis and SOD and MDA levels determined oxidative status through SOD and Catalase and NO measurements. The addition of MPP⁺ resulted in a 32.74% decrease in cell viability at 48 h while simultaneously decreasing SOD and Catalase and NO levels and increasing MDA levels. The addition of 25 µM GA protected cells from damage by increasing their viability to 86.53% at 48 h and decreasing apoptotic cell numbers. Our results revealed that co-treatment with 25-50 µM GA effectively mitigated oxidative damage by preventing the depletion of catalase and NO levels. Furthermore, GA successfully reduced lipid peroxidation; specifically, 25 µM GA decreased MDA levels from 21.18 to 9.64 nM/mg protein at 48 h, thereby restoring the cellular antioxidant defense system against MPP+-induced oxidative stress. In conclusion, the present study demonstrates that GA exerts a significant neuroprotective effect in an in vitro PD model by modulating the endogenous antioxidant network and alleviating lipid peroxidation. By effectively reversing the depletion of crucial enzymes and reducing apoptosis, GA shows potential therapeutic efficacy against oxidative stress-associated neurodegeneration. These findings suggest that GA is a promising phytochemical candidate warranting further in vivo evaluation to clarify its long-term bioavailability and translational value.
Since the mid-1990s, there have been major advances in diagnosing and providing antiretroviral therapy (ART) for pregnant women living with HIV (WLWH) in both resource-rich and resource-limited settings. Initial progress was based on the 1994 landmark perinatal trial, which showed 67% reduction in vertical transmission among infants born to non-breastfeeding mothers in the United States when zidovudine was given during pregnancy, at labour/delivery and for 6 weeks after birth. International perinatal trials began testing "short-course" zidovudine regimens during late pregnancy and at labour/delivery to develop cost-effective, feasible and deliverable interventions for low-resource environments. More recent research has focused on the delivery of cost-effective combination triple ART during pregnancy and breastfeeding for WLWH. The latest trial results indicate that providing lifetime maternal ART at the time of antenatal diagnosis improves overall survival and decreases morbidity, while reducing vertical transmission to <1%. Translation of clinical trial results into successful widescale programme implementation remains a major challenge, particularly in low- and middle-income countries with high HIV seroprevalence and weak maternal and child health infrastructure. Interventions recommended earlier in the global epidemic are no longer adequate, but key points of the perinatal cascade of services remain crucial to both ensure successful HIV care for WLWH and maximize reductions in vertical transmission. Notable progress made in Botswana and Uganda is valuable to highlight country-led successes. Rapid HIV testing for pregnant women whose status is unknown, followed by immediate implementation of lifetime maternal ART, and linkage to long-term HIV care/treatment are essential. Counselling on adherence, as well as the use of long-acting ART regimens and holistic support for women's care, including psychosocial support, are also needed. A current major challenge has been the sudden reduction in international donor funding, which has had a significant negative impact on continuity and effective delivery of HIV care/treatment services. Much progress has been made in advancing HIV interventions and programmes for WLWH and pregnant and breastfeeding mothers. However, several challenges persist, which compromise delivery of effective interventions on the path to eliminate perinatal HIV transmission, and care/treatment remains suboptimal for WLWH, especially in resource-limited settings.
This study aimed to investigate the clinicopathological significance of pulmonary metastasis in breast cancer patients and to evaluate the prognostic outcomes of lung metastasis subtypes. A retrospective analysis was conducted on breast cancer patients who underwent lung nodule biopsy at Peking University Cancer Hospital between 2010 and 2024. We identified 180 biopsied patients. Analyses of receptor discordance and survival were performed in the 154 pulmonary metastasis cases and primary lung cancers were described only for differential diagnosis. Among 2,857 breast cancer patients with lung nodules, 180 (6.3%) underwent pathological confirmation, including 154 (85.6%) with breast cancer lung metastases and 26 (14.4%) with primary lung cancers. In 128 patients with complete receptor profiles, the overall discordance rate between primary and metastatic lesions was 18.0% (95% CI, 11.2-24.7). The discordance rates for ER, PR, and HER2 were 10.9%, 26.6%, and 10.9%, respectively. Based on metastatic receptor status, 73 (47.4%) patients were classified as HR+/HER2-, 44 (28.6%) as HER2+, and 37 (24.0%) as triple-negative, with 3-year overall survival rates of 95.9%, 94.1%, and 65.3%, respectively (P < 0.001). Lung biopsy is indispensable for reassessing receptor status to guide systemic therapy and for differentiating metastatic lesions from primary lung cancers. Receptor heterogeneity between primary and metastatic sites was observed, and survival outcomes varied across lung metastasis subtypes.
The gut-associated lymphoid tissue (GALT) serves as the main immunological interface between fish and their aquatic environment, playing a central role in defense, homeostasis, and adaptation. Over the past two decades, probiotics have gained recognition as powerful tools for enhancing GALT function in teleost fish, influencing immunity, gut microbiota composition, and overall health. While previous reviews have addressed specific aspects of probiotic applications in aquaculture, a comprehensive synthesis linking immunological, microbiological, molecular, nutritional, and practical perspectives has been lacking. This review fills that gap by integrating these diverse domains into a unified analysis of probiotic-GALT interactions. Evidence indicates that probiotics promote beneficial shifts in gut microbial communities, support mucosal immunity through modulation of key immune cell populations and immunoglobulins, and contribute to improved growth and disease resistance. Despite promising results, challenges remain in translating laboratory findings into consistent field-level outcomes, particularly regarding strain stability, delivery methods, and host-specific responses. Future research should prioritize standardized evaluation protocols, advanced formulation technologies, and sustainable implementation strategies. By bridging disciplinary boundaries, this review provides a foundation for optimizing probiotic use to advance fish health and sustainable aquaculture.
To investigate the effect of CT slice thickness on radiomic features (RFs) in terms of reproducibility and discriminative power, and to assess whether a deep learning-based CT slice synthesis (DLS) algorithm can mitigate the adverse effects associated with thick-slice CT. This retrospective multicenter study included 506 patients with lung nodules (245 benign, 261 malignant) from two independent cohorts, which were divided into a training set, internal validation set (IVS), and external validation set (EVS). Chest CT reconstructed at 1-mm and 5-mm slice thicknesses was analyzed. A DLS algorithm was applied to convert 5-mm CT into synthetic 1-mm CT. RFs were extracted from all CT types to construct radiomics models. Reproducibility was assessed using the concordance correlation coefficient (CCC) and compared with the Wilcoxon signed-rank test. Discriminative power was evaluated by the area under the receiver operating characteristic curve (AUC) and compared with DeLong's test. The CCCs of DLS 1-mm CT were 0.48 ± 0.37 and 0.49 ± 0.37 in Cohort 1 and Cohort 2, respectively, significantly higher than real 5-mm CT (all p < 0.001). Most RFs from 5-mm CT lacked reproducibility (CCC ≥ 0.85; 0.9% in both Cohort 1 and Cohort 2), whereas DLS 1-mm CT showed marked improvement (Cohort 1, 27.6%; Cohort 2, 26.9%). The discriminative power of RFs from DLS 1-mm CT was superior to that of 5-mm CT and non-inferior to real 1-mm CT, both in model construction and evaluation. CT slice thickness substantially influences the reproducibility and discriminative power of RFs, whereas the DLS algorithm effectively mitigates the limitations associated with thick-slice CT. Deep learning-based CT slice synthesis significantly reduces the slice thickness-related variability in radiomics feature reproducibility and discriminative power, providing a promising methodological approach to improve radiomics standardization and support its clinical translation. CT slice thickness variability substantially impairs radiomic feature reproducibility and discriminative performance, posing a major barrier to standardized radiomics analysis. Across two independent cohorts, deep learning-based slice synthesis mitigated the adverse effects of thick-slice CT on radiomic feature reproducibility and cross-thickness discriminative performance.
Tumor evolution is shaped by adaptive responses to metabolic and oxidative stress, rather than solely by genetic mutations. Ferroptosis is an iron-dependent mechanism of cell death driven by lipid peroxidation. This process acts both as a tumor suppressive barrier and as a selective pressure for tumor adaptation. Cancer cells that escape ferroptosis undergo metabolic and transcriptional reprogramming, resulting in enhanced antioxidant capacity and increased resistance to oxidative stress. These adaptative changes closely intersect with epithelial-mesenchymal transition (EMT), generating hybrid phenotypes enriched in cancer stem cell (CSC)-like properties. Concurrently, tunneling nanotubes (TNTs) emerge as stress-responsive intercellular communication networks that facilitate the transfer of mitochondria, metabolites and redox regulators, thereby enabling cooperative survival. Through this review, we outline an integrative framework connecting ferroptosis, EMT plasticity, TNT-mediated communication and CSC dynamics, offering insights into novel strategies to overcome therapeutic resistance, prevent metastatic dissemination and limit tumor relapse. It further highlights the current landscape of emerging biomarkers and therapeutic agents that may enable the translation of this integrated network as a target in cancer treatment.
Disruptive mood dysregulation disorder (DMDD) was introduced in DSM-5 in 2013 to address concerns about overdiagnosis of pediatric bipolar disorder in chronically irritable children. We examined population-level trends in DMDD and bipolar disorder diagnoses and psychotropic medication use in youth. We conducted an interrupted time-series analysis using electronic health record data from the TriNetX Global Collaborative Network spanning 2003-2025. Annual incidence rates were estimated for DMDD diagnosis, bipolar disorder diagnosis, antipsychotic prescribing, and mood stabilizer prescribing among patients aged 6-18 years. Segmented regression models were used to evaluate trends before and after the introduction of DMDD. Secondary analyses identified data-driven change points independent of the DSM-5 timeline. Following DMDD introduction, DMDD diagnoses increased steadily while bipolar disorder diagnoses declined. Antipsychotic and mood stabilizer prescribing did not show immediate changes and declined later in the study period. Data-driven analyses identified a change point in bipolar disorder diagnoses in 2009, several years before DMDD introduction, whereas prescribing change points occurred around 2021. Diagnostic and prescribing trends were therefore temporally dissociated. Changes in pediatric bipolar disorder diagnoses were not immediately associated with changes in psychotropic prescribing. The decline in bipolar diagnoses most likely reflects accumulating evidence against the validity of broad bipolar diagnoses in chronically irritable children, rather than a direct effect of DMDD's introduction. Changes in diagnostic labels do not automatically translate into changes in prescribing behaviors. Diagnostic trends should be interpreted with caution, particularly when the validity of the diagnostic categories themselves remains unclear.
Parkinson's disease (PD) exhibits highly heterogeneous clinical trajectories, yet "advanced PD" (aPD) lacks a standardized definition. Current reliance on clinical milestones (e.g., motor fluctuations, cognitive decline) is limited by non-linear progression and the absence of objective measures. Although biomarkers like aggregated α-synuclein, MRI, and PET are under investigation, their correlation with clinical progression remains modest. Robust, reproducible endpoints are urgently needed to evaluate disease-modifying therapies across diverse phenotypes, accounting for genetic background, age of onset, co-pathologies, and motor/autonomic/cognitive domains. Given this complexity, single-target interventions are likely insufficient. We propose a multi-domain therapeutic framework for aPD that integrates: (A) simultaneous targeting of key pathological cascades, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, neuroinflammation, and the gut-brain axis; (B) biology-driven patient stratification using emerging biomarkers to match subgroups with targeted interventions; and (C) systematic management of comorbidities and lifestyle factors, such as cardiovascular health and exercise, to enhance neuroresilience. Finally, advancing aPD care requires addressing systemic determinants, including global healthcare inequities, and prioritizing caregiver well-being. Mechanistically informed, patient-centered strategies that combine multi-target therapies with precision stratification and holistic support will be essential to modify disease progression and improve long-term outcomes.
The contribution of fatty acid oxidation (FAO) to colorectal cancer (CRC) progression has been recognized. However, the detailed mechanisms underlying FAO remain obscure. This study explored the influence of ring finger protein 14 (RNF14) on FAO and its related mechanisms in CRC. We found that RNF14 was up-regulated in CRC, which was positively associated with FAO level. High expression of RNF14 promoted FAO to facilitate growth of CRC cells in vitro and in vivo. Mechanistically, RNA binding motif protein 15 (RBM15)/YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated N6-methyladenosine (m6A) modification enhanced RNF14 translation. RNF14 reduced TATA-box binding protein associated factor 1 (TAF1) protein stability via promoting its ubiquitination. Moreover, TAF1 bound to PTEN-induced kinase 1 (PINK1) promoter to trigger its transcription. RNF14 knockdown or TAF1 overexpression repressed FAO of CRC cells, which was overturned by TAF1 or PINK1 silencing, respectively. In conclusion, RBM15/YTHDF1-mediated m6A modification of RNF14 mRNA contributed to FAO enhancement via ubiquitination of TAF1 to transcriptionally inhibit PINK1, thus promoting CRC progression.