Triple-negative breast cancer (TNBC) exhibits marked molecular heterogeneity, posing ongoing therapeutic challenges. Metabolic reprogramming, particularly through the Warburg effect, offers a promising therapeutic target for TNBC treatment. Data mining and machine learning identified (+)-miliusol as a promising candidate. Its direct target, eukaryotic initiation factor 3D (EIF3D), was validated through mass spectrometry-coupled cellular thermal shift assay (MS-CETSA), a biotinylated probe, and a proteolysis-targeting chimera (PROTAC) approach. EIF3D, an emerging oncoprotein and atypical translation initiation regulator, promotes tumor survival by selectively modulating protein synthesis. (+)-Miliusol demonstrates potent anti-proliferative and anti-migratory activity against TNBC in both in vitro and in vivo. Integrated proteomic and transcriptomic analyses revealed that (+)-miliusol suppresses TNBC progression through EIF3D-mediated translational regulation. Mechanistically, it disrupts the EIF3D-AlkB homolog 5 (ALKBH5)-glucose transporter type 4 (GLUT4) axis, EIF3D-HIF1α signaling, and the EIF3D-RuvB like AAA ATPase 1 (RUVBL1)-β-catenin pathway, thereby inhibiting glycolysis and metastasis while inducing ER stress-dependent apoptosis via caspase-12 and JNK activation. Additionally, (+)-miliusol blocks EIF3D-HIF1α and EIF3D-ALKBH3 interactions, impairing ATAD2/PAK1-regulated Warburg-effect networks and triggering autophagy-associated cell death. (+)-Miliusol induces TNBC cell death by selectively suppressing translation of critical glycolytic and metastatic regulators. These findings establish EIF3D-mediated translational control as a promising therapeutic avenue for TNBC treatment.

Hepatocellular carcinoma (HCC) has a dismal prognosis with limited therapeutic options, and drug repurposing is a promising anti-HCC strategy. Pyrimethamine (Pyr), an FDA-approved antifolate drug with potential antitumor activity, its molecular mechanism in HCC remains elusive. In this study, in vitro experiments (MTT, colony formation, flow cytometry) confirmed that Pyr dose-dependently inhibited Hep3B and Huh7 cell proliferation, induced DNA damage and G0/G1 cell cycle arrest, and downregulated CCND1 expression. Mechanistically, Pyr upregulated METTL14 to enhance global m6A modification, and METTL14 directly mediated the m6A modification of CCND1 mRNA; the modified CCND1 was specifically recognized by YTHDF2, leading to its mRNA degradation. Bioinformatic and clinical sample analyses verified that METTL14 was downregulated in HCC tissues and acted as a tumor suppressor in vitro. In HCC patient-derived xenograft (PDX) models, Pyr significantly suppressed tumor growth, upregulated METTL14 and YTHDF2 expression, downregulated CCND1, and exhibited no obvious organ toxicity. This study reveals that Pyr exerts anti-HCC activity by activating the METTL14/YTHDF2 axis to induce m6A-dependent CCND1 mRNA degradation and subsequent G0/G1 arrest, uncovers a novel epitranscriptomic mechanism of Pyr, and supports its repurposing as a potential therapeutic agent for HCC.

The clinical relevance of mitochondrial RNA modification (MRM) in colorectal cancer (CRC), particularly its value for prognostic stratification, has not been fully defined. We integrated bulk transcriptomic profiles, machine learning-based model screening, single-cell analysis, and experimental validation to identify MRM score-associated prognostic genes and construct a CRC risk model. Seven CRC-related prognostic genes were selected: SPARCL1, MGP, PRELP, PALMD, TNS1, ARHGEF25, and PTGIS. These genes were incorporated into a risk signature with favorable prognostic performance, as supported by nomogram-based assessment. Gene Set Enrichment Analysis indicated that cytokine-related processes may participate in CRC progression. TNS1 showed the strongest positive association with natural killer cells (cor = 0.784, P < 0.05) and the strongest inverse association with type 17 T helper cells (cor = -0.279, P < 0.05). Database-based screening predicted 113 candidate compounds targeting CRC. Single-cell analysis further highlighted smooth muscle cells, epithelial cells, endothelial cells, T cells, and B cells as major cellular populations of interest. SPARCL1, MGP, PRELP, and PALMD increased during both early and late B cell maturation, whereas TNS1 and ARHGEF25 were highly expressed across broader cellular contexts. In conclusion, SPARCL1, MGP, PRELP, PALMD, TNS1, ARHGEF25, and PTGIS may represent MRM score-associated prognostic markers in CRC and require further study.

The darkbarbel catfish (Pelteobagrus vachelli) is an economically important aquaculture species in Asia, characterized by sexual dimorphism in growth between females and males. All-male breeding holds significant potential for aquaculture, but the sex-determining mechanism in this species remains unknown, and no sex-specific markers are available to differentiate males from females during the juvenile stage. In this study, whole-genome resequencing was applied to 60 individuals to identify genetic loci associated with sex, and the resulting data were analyzed using genome-wide association studies (GWAS) and FST analyses. For the first time, a total of 1435 SNPs and 461 InDels were identified on chromosome 3 significantly associated with sex, with these markers concentrated within a 17.1 Mb region. Within this region, male individuals exhibit heterozygosity SNPs, whereas females are homozygous, confirming an XX/XY sex-determination system. Based on InDel variations, two sexspecific markers were successfully developed, which can identify male and female individuals. Additionally, 300 genes were identified within the sex-determining region on chromosome 3, and transcriptomic data validated four potential candidate genes for sex determination, including sox11, hsf2, esr1, and pbk. Among these, sox11 and hsf2 may be involved in gonadal development as primary candidate sex-determining genes and may play critical roles in sex differentiation, thereby providing novel insights into the evolutionary mechanisms of sex chromosomes in this species. These findings present the first identification of a sex-linked marker in the darkbarbel catfish through whole-genome resequencing, offering valuable perspectives on the sex determination mechanism and the potential for all-male breeding in this species.

BackgroundParkinson’s disease (PD) is a progressive neurodegeneration disease characterized by dopaminergic (DA) neuron loss, with chronic neuroinflammation. Subthalamic nucleus deep brain stimulation (STN-DBS) is clinically effective for the relief of parkinsonism motor symptoms. Here, we used a homemade device to investigate the effect of STN-DBS on neuroprotection and chronic neuroinflammation in a unilateral 6-hydroxydopamine (6-OHDA)-induced PD rat model.MethodMale Sprague–Dawley rats received 6-OHDA injections into the striatum, followed by ipsilateral STN electrode implantation and high-frequency stimulation. Motor function was assessed by open-field and apomorphine-induced rotation tests. DA neuron survival, glial phenotype changes, and nuclear factor (NF)-κB pathway activity in the nigrostriatal system were evaluated using Western blotting, immunofluorescence, and RT-qPCR.ResultsSTN-DBS improved motor deficits and decreased the loss of tyrosine hydroxylase-positive neurons. It promoted astrocytes presented a neuroprotective phenotype and increased expression of brain-derived neurotrophic factor, and microglia mainly presented an anti-inflammatory M2 phenotype instead of a pro-inflammatory M1 phenotype. These effects may be associated with IκB-α stabilization, the suppression of NF-κB hyperactivation, and the consequent reduction in the release of downstream pro-inflammatory cytokines.ConclusionOur findings highlight that our homemade device for STN-DBS is capable of inhibiting NF-κB, modulating glial phenotypes, mitigating neuroinflammation, and ultimately ameliorating parkinsonism deficits.

Parkinson disease (PD), the second most common neurodegenerative disorder, is pathologically linked to dysregulated autophagy, a conserved lysosomal degradation pathway. Current conventional PD therapies are often limited by significant side effects, underscoring the demand for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to address this unmet clinical need. Here, by integrating clinical data analysis, we identified an association between autophagy impairment and specific PD patient subtypes, suggesting that ULK1-dependent autophagy activation may offer therapeutic benefit. Through systematic screening for autophagy induction and neuroprotective activity, we identified econazole, a known imidazole antifungal, as a promising candidate. Econazole exhibited robust therapeutic effects across multiple PD models, including MPTP-induced zebrafish and mouse models, as well as SNCAA53T mutant mouse models. Notably, its efficacy was dependent on functional autophagy, as autophagy inhibition abrogated its beneficial effects. Mechanistically, econazole activated ULK1, enhanced autolysosome formation, and promoted clearance of SNCA aggregates. Mouse brain microarray analysis indicated that econazole-activated ULK1 suppresses MAP3K12/DLK-MAPK8/JNK-MAPK9/JNK2-mediated neuronal apoptosis. Further phosphoproteomic profiling uncovered a novel ULK1-HSPA8/Hsc70 interaction that promotes LAMP1 and LAMP2 activation and enhances lysosomal function. This ULK1-HSPA8 complex additionally activated the BECN1 (beclin 1) complex to facilitate autophagosome formation. Together, our findings highlight a clinical data-guided drug repurposing approach that identifies econazole as a potent autophagy activator with therapeutic efficacy in ULK1-linked PD models, opening new avenues for PD treatment.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG: autophagy related; AUC: area under the curve; BafA1: bafilomycin A1; BECN1: beclin 1; CMA: chaperone-mediated autophagy; DA: dopamine; DOPAC: 3,4-dihydroxyphenylacetic acid; Econ: econazole; GFP: green fluorescent protein; HEK-293T: human embryonic kidney 293T; HSPA8: heat shock protein 8 family A (Hsp70) member 8; HVA: homovanillic acid; JUN: Jun proto-oncogene, AP-1 transcription factor subunit; KSEA: kinase-substrate enrichment analysis; LAMP: lysosome associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2K: mitogen-activated protein kinase kinase; MAP3K12: mitogen-activated protein kinase kinase kinase 12; MAPK: mitogen-activated protein kinase; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD: Parkinson disease; RB1CC1: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RMSD: root mean square deviation; SEM: standard error of the mean; SNCA: synuclein alpha; SQSTM1: sequestosome 1; SYP: synaptophysin; TFEB: transcription factor EB; TH: tyrosine hydroxylase; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

Broad-spectrum antibiotics profoundly disrupt the commensal microbiota and compromise mucosal immunity, creating a vulnerable postantibiotic window that predisposes hosts to opportunistic infections such as Pseudomonas aeruginosa. Strategies for restoring host homeostasis and stimulating mucosal immunity during this period remain limited. Here, we developed a modular and programmable probiotic strategy based on engineered Escherichia coli Nissle 1917 (EcN) that integrates metabolite replenishment with antigen-specific mucosal immunization. The butyrate-overproducing strain restored immune homeostasis after antibiotic exposure, enhanced baseline pulmonary neutrophil levels, and promoted bacterial clearance upon P. aeruginosa challenge. Additionally, synthetic EcN strains were engineered to release outer-membrane vesicles displaying P. aeruginosa antigens (PcrV or OprL), eliciting a robust pathogen-specific mucosal immunity. In antibiotic-exposed mice, metabolite and immunization modules independently reduced the pulmonary bacterial burden and improved survival following P. aeruginosa infection. Combined administration exerted synergistic protection, resulting in higher survival than the butyrate-overproducing strain alone under a lethal P. aeruginosa challenge. Together, this work establishes a versatile synthetic biology framework in which independently engineered probiotic modules can be flexibly combined to regulate microbiota function and deliver targeted immunotherapy, offering a promising alternative to antibiotic-dependent infection control.

Circular RNAs are a class of non-coding RNAs that are widely expressed in eukaryotes and are characterized by tissue-specific and developmental stage-specific expression. In recent years, circular RNAs have garnered significant attention in the field of RNA biology. The abundant expression and stability of circular RNAs in brain tissue make them highly promising for research in neuroscience and clinical diagnostics. The purpose of this review is to explore the distribution and function of circular RNAs in brain tissue, their roles in neurological disorders, and to summarize the potential of circular RNAs as biomarkers for neurodegenerative disorders. Circular RNAs are widely expressed in brain tissue, with the highest levels observed in the fetal brain, and they are closely associated with the development and function of the nervous system. Circular RNAs play important roles in synaptic development, synaptic function, memory, and cognitive abilities, and they are involved in the pathogenesis of various neurodegenerative diseases by regulating pathways such as miRNA. Circular RNAs, due to their stability, can serve as potential biomarkers for neurological diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral infarction. The expression changes of circular RNAs in these diseases have the potential for diagnosis and disease progression prediction, as these diseases are related to synaptic dysfunction and the decline of memory and cognitive abilities. Studying the role of circular RNAs in synaptic function and neurodegenerative diseases can help uncover the molecular mechanisms of neurodegenerative diseases and provide new strategies for precision medicine. The clinical application potential of circular RNAs as biomarkers needs further validation to realize their use in the early diagnosis and treatment of neurological diseases.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a poor prognosis and limited treatment options. Current clinical management relies primarily on surgical resection and adjuvant chemotherapy, underscoring the urgent need for novel therapeutic strategies. Through systematic pharmacological screening, we reveal that fenticonazole, a widely used imidazole antifungal, functions as a potent suppressor of TNBC cell growth. Mechanistic studies revealed that fenticonazole directly binds to NF-κB p105, impairing its processing into p50. Consequently, the formation of the p50-p65 heterodimer is suppressed, accompanied by enhanced p65 activation and inhibition of NRF2 transcription. These molecular alterations drive the accumulation of mitochondrial reactive oxygen species (ROS), resulting in endoplasmic reticulum (ER) stress and ultimately apoptosis in TNBC cells. Our results not only elucidate a previously unrecognized antitumor mechanism of fenticonazole but also provide a compelling rationale for its drug repurposing as a promising therapeutic option for TNBC.

Epigenetic regulators exert critical functions in cancer initiation and progression by governing key processes-such as gene expression, chromatin remodeling, and cellular differentiation-without altering the underlying DNA sequence. Given the multitude of targetable nodes within epigenetic pathways and their central roles in tumorigenesis, disease progression, and drug resistance, the advancement of epigenetic therapies holds considerable promise for augmenting existing cancer treatment modalities. Recent pharmacological innovations have yielded diverse small-molecule inhibitors directed against principal epigenetic enzymes-namely DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs). These agents have demonstrated potent therapeutic efficacy in both preclinical models and early-phase clinical trials by reprogramming the epigenetic landscape of malignant cells, potentiating conventional therapies, and overcoming resistance mechanisms. However, comprehensive assessments of their safety, selectivity, and resistance profiles remain incomplete, and systematic analyses of the clinical translation barriers for multitargeted epigenetic modulators are lacking. Accordingly, this review presents an in-depth analysis of the most recent advances in small-molecule epigenetic modulators, focusing on their mechanisms of action, therapeutic applications, and the challenges impeding their clinical development, with the aim of informing the rational design and optimization of next-generation epigenetic treatment strategies for cancer. FACTS.

Triple-negative breast cancer (TNBC) remains a challenging malignancy due to its aggressive nature and lack of targeted therapies. Miliusol, a natural product isolated from Miliusa tenuistipitata, exhibits potent anti-proliferative activity against TNBC but suffers from non-selective cytotoxicity. In this study, we employed a selective cytotoxicity-guided strategy to design and synthesize two novel series of Miliusol derivatives. MM-13 displayed enhanced tumor-selective cytotoxicity and demonstrated superior anti-proliferative and anti-migratory effects in TNBC cell lines compared to Miliusol, while showing minimal toxicity toward non-tumorigenic MCF-10A cells. Mechanistic studies revealed that MM-13 could inhibit glycolysis and induce DNA damage and apoptosis via the AKT/mTOR pathway. Importantly, MM-13 significantly suppressed tumor growth and metastasis in a 4T1 murine model without observable systemic toxicity. Our findings have enhanced the structure-activity relationship of Miliusol-type compounds and identify MM-13 as a promising candidate for TNBC-targeted therapy, offering a rational approach for improving natural product-derived anticancer agents.

Exosomes and plant-derived exosome-like nanoparticles (PELNs) are increasingly investigated as biologically derived nanocarriers that can couple cargo protection with biointerface-enabled transport. From a pharmaceutics standpoint, their therapeutic performance is often cargo-governed (e.g., microRNAs and proteins) and is ultimately constrained by delivery determinants such as stability, biodistribution, cellular uptake, and intracellular trafficking. In this review, we compare animal-derived exosomes (ADEs) and PELNs through a formulation-centric lens, emphasizing how source-dependent molecular composition shapes critical delivery behaviors and translational feasibility. We reorganize representative preclinical evidence into pharmaceutics-relevant delivery scenarios-including systemic/vascular targeting, blood-brain barrier transport, oral gastrointestinal delivery, and tumor microenvironment modulation-to connect cargo identity with exposure-site interactions and pharmacodynamic outcomes. We further discuss engineering strategies for improving payload control, targeting precision, and dosing accuracy, including endogenous enrichment, exogenous loading, and surface functionalization, while highlighting scale-up and safety considerations introduced by modification. Finally, we delineate translational priorities required to advance exosome-based products toward clinical development: standardized dose metrics (particle- and cargo-normalized), quantitative PK/biodistribution-PD relationships, potency assays and critical quality attributes (CQAs), manufacturing consistency under GMP, and regulatory-compliant characterization. Collectively, this review reframes ADEs and PELNs as cargo-driven pharmaceutical delivery systems and provides a practical roadmap for translation, with particular attention to the oral and scalable potential of PELNs.

Mitochondria are essential regulators of cell metabolism, apoptosis, and oxidative stress, rendering them critical targets for cancer therapy. This review systematically dissects the multifaceted roles of mitochondrial dysfunction in triple-negative breast cancer (TNBC), including its contributions to tumor initiation, progression, metabolic reprogramming, immune evasion, and programmed cell death, as well as its communication with other organelles. We summarize the current landscape of mitochondria-targeted therapeutic strategies for TNBC, encompassing direct targeting of mitochondrial proteins, indirect modulation of mitochondrial function via signaling pathways, mitochondria-targeted modification, and drug combination regimens. Additionally, we examine emerging approaches such as nanoparticle delivery systems and clinical compounds with mitochondrial regulatory effects. This review aims to provide a comprehensive framework for advancing the development of more precise and effective mitochondria-targeted therapies against TNBC.

Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H2S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H2S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H2S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H2S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H2S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H2S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction.

Objective: To systematically study the mechanisms by which Yinzhihuang (YZH), a traditional Chinese medicine, ameliorates intrahepatic cholestasis of pregnancy (ICP), a liver disorder associated with significant maternal and fetal complications.Methods: This experimental study was conducted from January 2024 to August 2024, utilizing data from public databases (Traditional Chinese Medicine Systems Pharmacology, GeneCards, Online Mendelian Inheritance in Man, DisGeNET, Proteome Xchange) alongside in vitro cell culture experiments. Network pharmacology identified active components of YZH and potential therapeutic targets for ICP. Ultra-performance liquid chromatography–mass spectrometry characterized YZH oral liquid, and its effective doses were evaluated in taurocholic acid (TCA)-induced HTR-8/SVneo cells, an in vitro ICP model. ICP-related targets were gathered from multiple databases, and hub genes were selected through bioinformatics and previously identified differentially expressed proteins. Functional annotation and pathway enrichment analyses were conducted, with validation in TCA-induced cells treated with various YZH concentrations (0.1%–5.0%) compared to controls. Molecular docking confirmed predicted interactions.Results: Using network pharmacology, 104 active compounds and 241 potential targets of YZH were identified. Integration of multiple databases yielded 1897 YZH-related therapeutic targets and 3783 ICP-associated genes. Proteomic analysis identified 227 differentially expressed proteins, from which 10 hub genes were selected; among these, APOA2, COL1A1, and ADIPOQ were significantly upregulated in ICP samples. UPLC-ESI-MS/MS detected 2022 compounds, predominantly flavonoids (25.07%, 507/2022) and phenolic acids (14.44%, 292/2022). Molecular docking demonstrated strong binding affinities between several active compounds and the hub genes. In TCA-induced HTR-8/SVneo cells, 0.5% YZH treatment significantly enhanced cell viability and modulated hub gene expression, supporting a potential multi-target mechanism.Conclusion: This study systematically explored the active components and potential targets of YZH in ICP through network pharmacology, proteomics, and in vitro validation. The findings suggest that YZH may act via the PPAR signaling pathway by modulating genes such asPPARA,PPARG,ADIPOQ, andAPOA2.

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.

Aging and cancer share overlapping characteristics, referred to as meta-hallmarks, which elucidate the convergent, antagonistic, or contradictory relationships between aging and cancer. Likewise, as a key characteristic of aging, senescent cells share some meta-hallmarks with tumor cells. These hallmarks include apoptosis resistance, metabolic alterations, secretory phenotypes, epigenetic reprogramming, and immune surveillance, all of which play pivotal roles in both tumorigenesis and senescence. Moreover, senolytic drugs, which are a class of agents selectively designed to eliminate senescent cells, have emerged as promising therapeutic agents in oncology and aging-related diseases. Since the discovery of the first senolytic drug in 2015, a diverse array of such agents has been developed. Notably, most senolytic drugs are repurposed from existing anti-tumor therapies, leveraging their shared mechanisms with senescent cells and tumor cells. Thus, this review examines the similarities between senescent cells and tumor cells, providing a better understanding of the meta-hallmarks. Besides, we categorize existing senolytic drugs based upon meta-hallmarks and elucidate the potential molecular mechanisms underlying their effects. By integrating insights from cancer and senescence research, this work aims to inspire innovative strategies for senolytic drug discovery.

Gaucher disease (GD), the most common lysosomal storage disorder, is an autosomal recessive inherited disease caused by mutations in GBA1. It can be categorized into neuronopathic and non-neuronopathic types. We previously constructed mouse models carrying the Gba1 F213I point mutation and tamoxifen-inducible systemic Gba1 knockout mice, both of which developed disease rapidly and had a short lifespan. This study combined these two models to create Gba1flox/F213I; UBC-CreERT2 mice. These mice exhibited a significantly extended lifespan, along with splenomegaly, infiltration of Gaucher-like cells, and reduced β-glucocerebrosidase (GCase) activity. Additionally, they displayed chronic neuroinflammation. In the later stages, these mice also exhibited typical pathological features of Parkinson's disease (PD), including a reduction in dopaminergic neurons in the substantia nigra pars compacta (SNpc) and an increase in the expression levels of the α-synuclein (α-syn) protein. RNA sequencing (RNA-seq) from the brain tissues of these mice revealed an early, robust inflammatory response, particularly with the activation of the interferon pathway, including the downstream expression of MHC I complex molecule genes, which was confirmed through Western blot analysis. In summary, we established a chronic neurogenic Gaucher disease mouse model that exhibited pronounced inflammatory activation and developed Parkinsonian-like phenotypes in the later stages.

Supplemental materials and methods

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and addressing its intrinsic heterogeneity has emerged as a valuable avenue for novel clinical treatment strategy. Here, we put forward an innovative strategy for TNBC treatment by simultaneously suppressing both p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10). A series of pyrido [2,3-d]pyrimidin-7(8H)-one moiety derivatives was successfully designed and synthesized to target PAK1/HDAC6/HDAC10 by utilizing structure-based screening and pharmacophore integration. ZMF-25 demonstrates marked inhibitory activity against PAK1, HDAC6, and HDAC10 with respective IC50 values of 33, 64, and 41 nM, remarkable selectivity over HDACs and PAKs, as well as prominent antiproliferative efficiency in MDA-MB-231 cells. Additionally, ZMF-25 effectively suppresses TNBC proliferation and migration by inhibiting PAK1/HDAC6/HDAC10. Moreover, it was found to impair glycolysis and trigger reactive oxygen species generation, resulting in autophagy-related cell death by inhibiting the AKT/mTOR/ULK1 signaling. Furthermore, ZMF-25 exhibits remarkable therapeutic potential with no obvious toxicity in vivo and good pharmacokinetics. In summary, these observations indicate that ZMF-25 is a novel and potent triple-targeting PAK1/HDAC6/HDAC10 inhibitor, which is expected to provide a novel and effective strategy for TNBC treatment.