Enterovirus A71 (EV-A71) is a positive-sense single-stranded RNA virus, which hijacks host proteins to benefit viral internal ribosome entry site (IRES)-dependent protein translation and further propagation. We demonstrated that serine 78 (S78) phosphorylation of Hsp27 is critical for Hsp27/hnRNP A1 relocalization upon EV-A71 infection. Here, we report that the deletion of WDPF and ACD domains disturbs subcellular localization of Hsp27, resulting in partial nuclear translocation. The domain deletion-induced Hsp27 nuclear translocation fails to direct hnRNP A1 translocation. The 2A^pro-induced IRES activity and viral replication are suppressed by the deletion of WDPF or ACD domain. Surprisingly, a peptide (WDPF) dramatically inhibits S78 phosphorylation. Therefore, hnRNP A1 translocation, viral IRES activity, and viral protein translation and propagation are all strongly suppressed by the WDPF peptide, but not by peptide without WDPFR sequence (ΔWDPF). Moreover, the WDPF peptide also has potent antiviral activity on other RNA virus (e.g., coronavirus HCoV-OC43) and DNA virus (e.g., HSV-1 and HBV). Peptide treatment with kinase inhibitor Sorafenib brings an additional inhibitory effect on HCoV-OC43 and HSV-1. Taken together, we uncover a crucial role of WDPF domain in S78 phosphorylation for EV-A71-induced hnRNP A1 nuclear translocation, IRES-dependent viral protein translation, and EV-A71 propagation. Our results explore a new path for target-based pan-antiviral strategy.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impact of key factors leading to cellular senescence on tumorigenesis. In addition, this review summarizes the current intervention strategies targeting nutrient sensing pathways, as well as the clinical cases of treating tumors targeting the characteristics of senescence with the existing nanodelivery research strategies. Finally, it also suggests sensible dietary habits for those who wish to combat aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.

Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria–lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide-binding protein 2 (HINT2) in DOX-induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX-treated mice. Cardiac-specific Hint2 knockout mice exhibited significantly worse cardiac dysfunction, impaired autophagic flux, and lysosomal dysfunction after DOX treatment. Mechanistically, HINT2 deficiency reduced oxidative phosphorylation complex I activity and disrupted the nicotinamide adenine dinucleotide NAD⁺/NADH ratio, impairing lysosomal function. Further, HINT2 deficiency suppressed sterol regulatory element binding protein 2 activity, downregulating transcription factor A mitochondrial, a critical regulator of complex I. Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro, while cardiac-specific Hint2 overexpression using adeno-associated virus 9 or adenovirus alleviated DIC both in vivo and in vitro. These findings highlight HINT2 as a key cardioprotective factor that mitigates DIC by restoring the NAD⁺/NADH ratio, lysosomal function, and autophagy. Therapeutic strategies enhancing HINT2 expression or supplementing NMN may reduce cardiac damage and heart failure caused by DOX.

The integration of liquid biopsy with epigenetic markers offers significant potential for early lung cancer detection and personalized treatment. Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA changes, often precede genetic mutations and are critical in cancer progression. In this study, we explore how liquid biopsy, combined with epigenetic markers, can provide early detection of lung cancer, potentially predicting onset up to 4 years before clinical diagnosis. We discuss the challenges of targeting epigenetic regulators, which could disrupt cellular balance if overexploited, and the need for maintaining key gene expressions in therapeutic applications. This review highlights the promise and challenges of using liquid biopsy and epigenetic markers for early-stage lung cancer diagnosis, with a focus on optimizing treatment strategies for personalized and precision medicine.

Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.

Protein palmitoylation, a reversible post-translational lipid modification, is catalyzed by the ZDHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases, regulating protein localization, accumulation, secretion, and function. Neurological disorders encompass a spectrum of diseases that affect both the central and peripheral nervous system. Recently, accumulating studies have revealed that pathological protein associated with neurological diseases, such as β-amyloid, α-synuclein, and Huntingtin, could undergo palmitoylation, highlighting the crucial roles of protein palmitoylation in the onset and development of neurological diseases. However, few preclinical studies and clinical trials focus on the interventional strategies that target protein palmitoylation. Here, we comprehensively reviewed the emerging evidence on the role of protein palmitoylation in various neurological diseases and summarized the classification, processes, and functions of protein palmitoylation, highlighting its impact on protein stability, membrane localization, protein–protein interaction, as well as signal transduction. Furthermore, we also discussed the potential interventional strategies targeting ZDHHC proteins and elucidated their underlying pathogenic mechanisms in neurological diseases. Overall, an in-depth understanding of the functions and significances of protein palmitoylation provide new avenues for investigating the mechanisms and therapeutic approaches for neurological disorders.

Oraxol, a novel oral paclitaxel chemotherapy agent, has emerged as a potential alternative for treating metastatic breast cancer (MBC). However, its safety and efficacy remain uncertain due to insufficient evidence supporting it. This open-label, single-arm, phase I trial was designed to assess the pharmacokinetics, safety, and preliminary antitumor activity of Oraxol in previously treated MBC. The primary objective was to investigate the pharmacokinetics of Oraxol, while secondary endpoints included assessing safety, tolerability, and antitumor activity. Twenty-four patients (median age, 53 years) were enrolled, and pharmacokinetic analysis showed consistent and reproducible absorption of Oraxol. Note that 96% patients experienced treatment-related adverse events (TRAEs) and no deaths attributed to TRAEs. The overall response rate was 34.8%, including 34.8% achieving partial response and 56.5% having stable disease. The median follow-up was 45.7 months, with median progression-free survival (PFS) of 3.41 months and median overall survival of 17.80 months. Notably, among patients with triple-negative breast cancer, the disease control rate was 100%, and the median PFS was 8.90 months, which notably exceeded the outcomes observed in other subtypes. Oraxol significantly alters metabolism and correlates with response and survival. In conclusion, Oraxol exhibited promising antitumor efficacy and manageable safety profiles in MBC patients.

Whether low peripheral oxygen saturation (SpO₂) directed oxygen therapy is associated with lower mortality in critically ill patients needs further exploration. Adult critically ill patients from 11 intensive care units in China were screened. Participants were randomly assigned to the low SpO₂ (90%–95%) group or the high SpO₂ (≥96%) -group. The primary outcome was 28-day all-cause mortality. The secondary outcomes were hours free from ventilators and from renal replacement therapy (RRT) within 14 days. Note that 857 patients in the low SpO₂ group and 849 in the high SpO₂ group were included. In the low SpO₂ group versus the high SpO₂ group, the time-weighted average of the fraction of inspired oxygen (FiO₂) was significantly lower (33.5 ± 9.7% vs. 39.6 ± 9.3%, p < 0.001), and so was the time-weighted average of SpO₂ (95.9 ± 1.8% vs. 98.0 ± 1.9%, p < 0.001). Within 28 days after randomization, 172 (20.1%) in the low SpO₂ group and 193 (22.7%) in the high SpO₂ group died (p = 0.180). Ventilator-free time and RRT-free time were not significantly different within 14 days. In critically ill patients, low SpO₂directed oxygen therapy did not decrease 28-day mortality, 14-day ventilator-free time, or 14-day RRT-free time.

Compared with traditional treatment strategies, siRNA-based gene therapy combines with protein therapy to offer a new strategy for spinal cord injury (SCI). The siRNA and protein therapy are limited by the large and deep lesion site and local co-delivery vectors. However, the photocurable scaffold has the properties of injectable, flexible, and biodegradable, which provide a potential formulation for siRNA and protein combined therapy. Here, a photocurable lipid nanoparticle gel (PLNG) scaffold is designed for efficiently sustained and controlled release of the macrophage migration-inhibitory factor (MIF) targeted siRNA and co-delivery of GDNF protein for SCI. The GDNF is chemically modified in the scaffold and the prepared GDNF-PLNG/siRNA scaffold is injectable with easily photocured. This formulation can inhibit inflammation by promoting macrophage M2 polarization and effectively promote primary neuron axon growth. After locally administered with GDNF-PLNG/siMIF scaffold to SCI mice, the scaffold promoted neuron regeneration by upregulation of neuron cytokine production and inhibited inflammation through the downregulation immune pathway. With the interaction mechanism of GDNF and MIF siRNA, GDNF-PLNG/siMIF scaffold increases the collagen and integrin expression to promote spinal cord repairing and significantly improve motor function, so that scaffold is a potential candidate gene formulation applied to clinical SCI treatment.

Chemotherapy combined with checkpoint blockade antibodies targeting programmed cell death protein (PD-1) has achieved remarkable success in non-small cell lung cancer. However, few patients benefit from long-term treatment. Therefore, biomarkers capable of guiding the optimal therapeutic selection and reducing unnecessary toxicity are of pressing importance. In our research, we gathered serial blood samples from two groups of non-small cell lung cancer patients: 49 patients received a combination of therapies, and 34 patients went under chemotherapy alone. Utilizing non-targeted metabolomic analysis, we examined different metabolites’ disparity. Among the lot, L-phenylalanine emerged as a significant prognostic marker in the combination treatment of non-small cell lung cancer patients, interestingly absent in patients under sole chemotherapy. The reduced ratio of L-phenylalanine concentration (two-cycle treatment vs. pre-treatment) was associated with improved progression-free survival (hazard ratio = 1.8000, 95% confidence interval: 0.8566–3.7820, p < 0.0001) and overall survival (hazard ratio = 1.583, 95% confidence interval: 0.7416–3.3800, p < 0.005). We further recruited two validation cohorts (cohort 1: 40 patients and cohort 2: 30 patients) to validate the sensitivity and specificity of L-phenylalanine prediction. Our results demonstrate that a model based on L-phenylalanine variations could serve as an early risk-assessment tool for non-small cell lung cancer patients undergoing treatment, potentially facilitating strategic clinical decision-making.

Neutrophil extracellular traps (NETs) are unique fibrous structures released by neutrophils in response to various pathogens, exhibiting both anti-inflammatory and proinflammatory effects. In autoimmune conditions, NETs serve as crucial self-antigens triggering inflammatory cascades by activating the inflammasome and complement systems, disrupting self-tolerance mechanisms and accelerating autoimmune responses. Furthermore, NETs play a pivotal role in modulating immune cell activation, affecting adaptive immune responses. This review outlines the intricate relationship between NETs and various diseases, including inflammatory arthritis, systemic autoimmune diseases, Behçet’s disease, systemic lupus erythematosus, autoimmune kidney diseases, autoimmune skin conditions, systemic sclerosis, systemic vasculitis, and gouty arthritis. It highlights the potential of targeting NETs as a therapeutic strategy in autoimmune diseases. By examining the dynamic balance between NET formation and clearance in autoimmune conditions, this review offers critical insights and a theoretical foundation for future research on NET-related mechanisms. Advances in systems biology, flow cytometry, and single-cell multiomics sequencing have provided valuable tools for exploring the molecular mechanisms of neutrophils and NETs. These advancements have renewed focus on the role of neutrophils and NETs in autoimmune diseases, offering promising avenues for further investigation into their clinical implications.

Anti-PD-1 immunotherapy and targeted therapy (TT) represent two major therapeutic modalities for BRAF^V600-mutant advanced melanoma, but the efficacy of combination therapy in Asian populations remains unknown. Asian melanoma patients differ significantly from Caucasians in tissue subtypes, pathogenesis and response to treatment. We retrospectively analyzed data of BRAF^V600-mutant advanced melanoma patients treated with first-line vemurafenib (V) ± anti-PD-1 or dabrafenib+trametinib (D+T) ± anti-PD-1 between 2014 and 2023 from three centers in China. 178 patients were included, with V (n = 45), D+T (n = 51), V+anti-PD-1 (n = 39) and D+T+anti-PD-1 (n = 43). The median PFS (21.9 vs. 11.1 months, p < 0.001), OS (NR vs. 32.6 months, p = 0.027), and DoR (20.0 vs. 8.4 months, p = 0.002) were significantly prolonged with D+T+anti-PD-1 versus D+T. Addition of anti-PD-1 to V also significantly prolonged PFS, OS, and DoR (p < 0.001). V+anti-PD-1 was superior to D+T in terms of PFS (15.0 vs. 11.1 months, p = 0.007) and DoR (18.0 vs. 8.4 months, p = 0.013), and was comparable to D+T+anti-PD-1. Addition of anti-PD-1 to BRAF inhibitor-based TT was associated with lower incidence of brain metastases (p = 0.032). Addition of anti-PD-1 to BRAF inhibitor-based TT appears to be a safe and effective treatment option, conferring a survival benefit and delaying the onset brain metastases in patients with BRAF^V600-mutant advanced melanoma.

Colorectal cancer (CRC) is among the most prevalent and deadly cancers worldwide. The Yes-associated protein 1 (YAP1) is frequently dysregulated in cancers, contributing to cancer stemness, chemoresistance, and cancer-related death. However, strategies directly targeting YAP1 have not yet been successful because of the lack of active binding pockets and unregulated toxicity. In this study, our Food and Drug Administration (FDA)-approved drug screening reveals that abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes the proteasome-dependent degradation of YAP1, thereby inhibiting tumor progression in CRC cells and patient-derived xenograft models. We further identify deubiquitinating enzyme 3 (DUB3) as the bona fide deubiquitinase of YAP1 in CRC. Mechanistically, CDK4/6 directly phosphorylates DUB3 at Ser41, activating DUB3 to deubiquitinate and stabilize YAP1. Conversely, loss of Ser41 phosphorylation by CDK4/6 inhibition or Ser41A mutation, promotes YAP1 degradation and suppresses YAP1-driven tumor progression. Histological analysis shows a positive correlation between DUB3 and YAP1 expression in CRC specimens. Collectively, our study uncovers a novel oncogenic role of the CDK4/6-DUB3 pathway, which promotes YAP1 stabilization and tumor-promoting function, highlighting that targeting CDK4/6 offers a potential therapeutic strategy for CRC with aberrantly upregulated DUB3 and YAP1.

Compelling evidence supports a link between early-life gut microbiota and the metabolic outcomes in later life. Using an early-life antibiotic exposure model in BALB/c mice, we investigated the life-course impact of prenatal and/or postnatal antibiotic exposures on the gut microbiome of offspring and the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Compared to prenatal antibiotic exposure alone, postnatal antibiotic exposure more profoundly affected gut microbiota development and succession, which led to aggravated endotoxemia and metabolic dysfunctions. This was primarily resulted from the overblooming of gut Parabacteroides and hepatic accumulation of cytotoxic lysophosphatidyl cholines (LPCs), which acted in conjunction with LPS derived from Parabacteroides distasonis (LPS_PA) to induce cholesterol metabolic dysregulations, endoplasmic reticulum (ER) stress and apoptosis. Integrated serum metabolomics, hepatic lipidomics and transcriptomics revealed enhanced glycerophospholipid hydrolysis and LPC production in association with the upregulation of PLA2G10, the gene controlling the expression of the group X secretory Phospholipase A2s (sPLA2-X). Taken together, our results show microbial modulations on the systemic MASLD pathogenesis and hepatocellular lipotoxicity pathways following early-life antibiotic exposure, hence help inform refined clinical practices to avoid any prolonged maternal antibiotic administration in early life and potential gut microbiota-targeted intervention strategies.

Chemoresistance is one main cause of failure in colorectal cancer (CRC) treatment. The role of transcription factor Ras-responsive element binding protein 1 (RREB1) remains unclarified in CRC chemoresistance. Herein, we reveal that RREB1 functions as an oncogene to promote cell proliferation and 5-fluorouracil (5-FU) chemoresistance in CRC, and SUMOylation is required for RREB1 to exert its oncogenic role in CRC. RREB1 induced cell cycle arrest at the S-phase and a decreased apoptosis rate under 5-FU exposure. Mechanistically, the interaction of RREB1 with lysine demethylase 1A (KDM1A) elevated expression of 5-FU targeting proteins thymidylate synthase (TS) and thymidine kinase (TK1) to maintain the nucleotide pool balance under 5-FU treatment, and enhanced activation of Chk1-mediated DNA damage response (DDR) pathway. The deSUMOylation of RREB1 resulted in a reduced interaction of RREB1 with KDM1A, contributing to a downregulation of TS expression and a less activation of DDR pathway. Moreover, KDM1A knockdown improved the DNA damage and reduced RREB1-mediated resistance to 5-FU. These findings provide new insights into RREB1-mediated chemotherapy responses in CRC and indicate RREB1 is a potential target for overcoming 5-FU resistance.

Bladder cancer’s high mortality underscores the need for precise staging, especially to differentiate between nonmuscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) types. This prospective study evaluated the efficacy of contrast-enhanced ultrasound (CEUS) for preoperative staging, focusing on its ability to distinguish NMIBC from MIBC. Conducted from April 2020 to September 2021, the study involved 163 patients (median age: 64.0 years; 137 males, 26 females), with 133 NMIBC (81.6%) and 30 MIBC (18.4%). Each patient underwent CEUS followed by transurethral resection of bladder tumor or radical cystectomy. CEUS demonstrated high diagnostic accuracy in determining muscle invasion status (sensitivity 83.3%, specificity 92.5%, accuracy 90.8%, area under the receiver operating characteristic curve [AUC] 0.88). Comparative analyses against MRI (AUC 0.77) showed CEUS outperforming in muscle invasion detection. Combining CEUS with MRI improved diagnostic accuracy, particularly when MRI vesical imaging reporting and data system score was 3 points. The combined approach achieved an AUC of 0.73, with sensitivity, specificity, and accuracy of 76.2, 70.2, and 71.6%, respectively. Thus, CEUS emerges as a valuable diagnostic tool for preoperative staging of bladder cancer, particularly in its role in assessing muscle invasion status and thereby aiding in clinical decision-making and intervention outcomes.

Stroke is a leading risk factor for disability and death. Necroptosis is involved in stroke pathogenesis. However, the molecular mechanisms underlying necroptosis in stroke remain unclear. The mammalian target of rapamycin complex 1 (mTORC1) modulates necroptosis in the gut epithelium. Eukaryotic translation initiation factor 4E (eIF4E)-binding protein-1 (4EPB1) is one of the main downstream molecules of mTORC1. This study addresses the role of the 4EBP1–eIF4E pathway in necroptosis. The 4EBP1–eIF4E pathway was found to be activated in both necroptotic HT-22 and mouse middle cerebral artery occlusion (MCAO) models. Functionally, 4EBP1 overexpression, eIF4E knockdown, and eIF4E inhibition suppressed necroptosis, respectively. Furthermore, a positive feedback circuit was observed between the 4EBP1–eIF4E and receptor-interacting protein-3 (RIP3)–mixed lineage kinase domain-like protein (MLKL) pathways, in which RIP3–MLKL activates the 4EBP1–eIF4E pathway by degrading 4EBP1 and activating eIF4E. This in turn enhanced RIP3–MLKL pathway activation. The eIF4E activation derived from this loop may stimulate cytokine production, which is a key factor associated with necroptosis. Finally, using a mouse MCAO model, the application of eIF4E, RIP3, and MLKL inhibitors was found to have a regulatory mechanism similar to that in the in vitro study, reducing the infarct volume and improving neurological function in MCAO mice.

Glioblastoma (GBM) exhibits significant intratumor heterogeneity (ITH), indicating the presence of tumor cells with diverse growth rates. Here, we aimed to identify fast-growing cells in GBM and elucidate the underlying mechanisms. Precisely targeting these cells could offer an improved treatment option. Our results found that targeting ALKBH5 expression impaired GBM proliferation and tumor stemness. Nuclear but not overall expression of ALKBH5 differs between monoclonal cells derived from the same patient with different proliferation rates. Mechanistically, ALKBH5 interacted with TAR DNA-binding protein 43 (TDP-43) in fast-growing cells. Furthermore, TDP-43 facilitated the nuclear localization of ALKBH5 and its binding to cell division cycle 25A (CDC25A) pre-mRNA. The TDP-43/ALKBH5 complex regulates CDC25A mRNA splicing via N6-methyladenosine (m⁶A) demethylation to maintain the expression of its oncogenic isoform (CDC25A-1), ultimately promoting the G1/S phase transition and growth of GBM cells. TRAD01 selectively targeted the interaction between TDP-43 and ALKBH5, leading to significant antitumor effects both in vitro and in vivo. Our study identified a novel epigenetic mechanism by which TDP-43/ALKBH5 contributes to GBM growth via m⁶A modification and alternative splicing. Therefore, targeting the TDP-43/ALKBH5 axis might be a promising therapeutic strategy for GBM patients.

The mortality rate of sepsis is approximately 22.5%, accounting for 19.7% of the total global mortality. Since Lewis Thomas proposed in 1972 that “it is our response that makes the disease (sepsis)” rather than the invading microorganisms, numerous drugs have been developed to suppress the “overwhelming” inflammatory response, but none of them has achieved the desired effect. Continued failure has led investigators to question whether deaths in septic patients are indeed caused by uncontrolled inflammation. Here, we review the history of clinical trials based on evolving concepts of sepsis pathogenesis over the past half century, summarize the factors that led to the failure of these historical drugs and the prerequisites for the success of future drugs, and propose the basic principles of preclinical research to ensure successful clinical translation. The strategy of targeting inflammatory factors are like attempting to eliminate invaders by suppressing the host’s armed forces, which is logically untenable. Sepsis may not be that complex; rather, sepsis may be the result of a failure to fight microbes when the force of an invading pathogen overwhelms our defenses. Thus, strengthening the body’s defense forces instead of suppressing them may be the correct strategy to overcome sepsis.

Prenatal dexamethasone exposure (PDE) can increase offspring susceptibility to various diseases. However, the pathogenesis and early prevention for PDE offspring prone to cholestatic liver injury have been unclear. In this study, we collected human umbilical cord blood from neonates with prenatal dexamethasone therapy, showing increased primary unconjugated bile acid levels in utero. PDE increased blood primary bile acid levels, enhanced endoplasmic reticulum stress, and led to cholestatic liver injury in adulthood in rats, which is accompanied by the persistent increase of H3K14ac level in cholesterol 27α-hydroxylase (CYP27A1) promoter and its expression before and after birth. In vitro, dexamethasone activates glucocorticoid receptors, binding to the CYP27A1 promoter, and promotes its transcriptional expression. Through the miR-450b-3p/SIRT1 pathway, it increased the H3K14ac level of the CYP27A1 promoter to enhance its transcription, which continues after birth. Finally, nilvadipine effectively reversed cholestatic liver injury induced by PDE. This study confirmed PDE could cause cholestatic liver injury, and innovatively proposed its early intervention target (CYP27A1) and effective drug (nilvadipine), providing a theoretical and experimental basis for guiding rational drug use during pregnancy, and preventing and treating the fetal-originated cholestatic liver injury.

Central and peripheral extensive-stage small-cell lung cancer (ES-SCLC) are reported to be two distinct tumor entities, but their responses to the front-line therapies and underlying biological mechanisms remain elusive. In this study, we first compared the outcomes of central and peripheral ES-SCLC receiving front-line chemotherapy or chemo-immunotherapy with a cohort of 265 patients. Then we performed single-cell RNA sequencing (scRNA-seq) on nine treatment-naïve ES-SCLC samples to investigate potential mechanisms underlying the response differences. Under chemotherapy, the peripheral type had a lower objective response rate (44.8% vs. 71.2%, p = 0.008) and shorter progression-free survival (median 3.4 vs. 5.1 months, p = 0.001) than the central type. When comparing chemo-immunotherapy with chemotherapy, the peripheral type showed a greater potential to reduce progression (HR, 0.18 and 0.52, respectively) and death (HR, 0.44 and 0.91 respectively) risks than the central type. Concerning the scRNA-seq data, the peripheral type was associated with chemo-resistant and immune-responsive tumoral and microenvironmental features, including a higher expression level of MYC-Notch-non-neuroendocrine (MYC-Notch-non-NE) axis and a more potent antigen presentation and immune activation status. Our results revealed that central and peripheral ES-SCLC had distinct responses to front-line treatments, potentially due to differential activation statuses of the MYC-Notch-non-NE axis.

The maintenance of endocrine homeostasis in the placenta is crucial for ensuring successful pregnancy. An abnormally elevated production of placental testosterone (T₀) has been documented in patients with early-onset preeclamptic (E-PE). However, the underlying mechanisms remain unclear. In this study, we found that E-PE placentas exhibited significantly increased expressions of 3β-HSD1 (3β-Hydroxysteroid Dehydrogenase 1) and 17β-HSD3 (17β-Hydroxysteroid Dehydrogenase 3), the rate-limiting enzymes for T₀ synthesis. This was strongly correlated with an elevated level of O-linked N-acetylglucosaminylation (O-GlcNAcylation) of GATA3 (GATA binding protein 3). In human trophoblast cells, O-linked-N-acetylglucosamine (O-GlcNAc) modification of GATA3 on Thr³²² stabilized the protein and enhanced the transcriptional regulation of 3β-HSD1 and 17β-HSD3, thereby increasing T₀ production. Hypoxia, a well-established pathological factor in PE, significantly enhanced the O-GlcNAcylation of GATA3 in human trophoblast cells. Our findings suggest that hypoxia-induced overactive O-GlcNAcylation of GATA3 contributes to the exacerbated T₀ production in E-PE placentas. These findings provide a new perspective on the pathogenesis of E-PE from the standpoint of posttranslational regulation and may illuminate novel therapeutic strategies for adverse pregnancy outcomes such as E-PE.

Ferroptosis is a distinct form of iron-dependent programmed cell death characterized primarily by intracellular iron accumulation and lipid peroxidation. Multiple cellular processes, including amino acid metabolism, iron metabolism, lipid metabolism, various signaling pathways, and autophagy, have been demonstrated to influence the induction and progression of ferroptosis. Recent investigations have elucidated that ferroptosis plays a crucial role in the pathogenesis of various pulmonary disorders, including lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. Ferroptosis is increasingly recognized as a promising novel strategy for cancer treatment. Various immune cells within the tumor microenvironment, including CD8+ T cells, macrophages, regulatory T cells, natural killer cells, and dendritic cells, have been shown to induce ferroptosis in tumor cells and modulate the process through the regulation of iron and lipid metabolism pathways. Conversely, ferroptosis can reciprocally alter the metabolic environment, leading to the activation or inhibition of immune cell functions, thereby modulating immune responses. This paper reviews the molecular mechanism of ferroptosis and describes the tumor immune microenvironment, discusses the connection between ferroptosis and the tumor microenvironment in lung cancer and pulmonary diseases, and discusses the development prospect of their interaction in the treatment of lung cancer and pulmonary diseases.

Intratumoral brachytherapy enables higher dose treatment and reduces damage to adjacent tissues. We first validated the feasibility and safety of endoscopic ultrasound (EUS)-guided Yttrium-90 (⁹⁰Y) microspheres implantation in a porcine model. Under EUS guidance, ⁹⁰Y-loaded microspheres were implanted into the pancreas of 10 miniature pigs. The first pig was implanted with 10 MBq particles. Subsequently, nine pigs were sequentially included in the low- (20 MBq), medium- (40 MBq), and high-dose (60 MBq) groups. Positron emission tomography (PET)/CT imaging was used to check the occurrence of particle displacement postoperatively. After euthanasia, the pancreas and adjacent organs were excised for histological examination and residue radiation detection. The absorbed doses demonstrated safe in the porcine model were further in the xenograft model and KRAS^LSL/+Trp53^FL/FLPtfqa^Cre/+ mouse model. EUS-guided implantations of ⁹⁰Y-loaded microspheres were successful in all animals. Two pigs had mild serum amylase elevation in the high-dose group and the abnormal index returned to baseline without interventions. The volume of necrotic lesions ranged from 255.76 to 745.57 mm³. In KPC mouse model, PET/CT imaging demonstrated a significant decrease in maximum standardized uptake value (SUVmax) after ⁹⁰Y implantation. EUS-guided ⁹⁰Y-loaded carbon microsphere implantation could serve as a safe and feasible technique at ultrahigh dose for pancreatic cancer brachytherapy.

Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remains controversial. Furthermore, the potential interaction between SIRT1 and receptor-interacting protein kinase 1 (RIP1) in this context is not fully understood. Sanpian Decoction (SPD), a classical traditional herbal formula, was previously shown to enhance SIRT1 expression in our studies. Our findings demonstrated that, both in vivo and in vitro, CIRI was associated with a decrease in SIRT1 levels and phosphorylated dynamin-related protein 1 (p-DRP1) at Ser637, alongside an increase in RIP1 and other necroptosis-related proteins. Co-immunoprecipitation and immunofluorescence analyses revealed a weakened interaction between SIRT1 and RIP1. Furthermore, abnormal mitochondrial fission and dysfunction were mediated through the phosphoglycerate mutase 5–DRP1 pathway. Notably, SPD treatment improved neurological outcomes and reversed these pathological changes by enhancing the SIRT1–RIP1 interaction. In conclusion, this study suggests that SIRT1 is a promising therapeutic target for CIRI, capable of inhibiting necroptosis and mitigating mitochondrial fission via the SIRT1–RIP1 pathway. SPD exhibits therapeutic potential by activating SIRT1, thereby attenuating necroptosis and mitochondrial fission during CIRI.

Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy of therapeutic interventions. In recent years, both preclinical and clinical research have made significant progress in understanding the molecular mechanisms and therapeutic strategies of liver metastasis. Metastatic tumor cells from different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization and growth in the liver. In this review, we begin by introducing the inherent metastatic-friendly features of the liver. We then explore the panorama of liver metastasis and conclude the three continuous, yet distinct phases based on the liver’s response to metastasis. This includes metastatic sensing stage, metastatic stress stage, and metastasis support stage. We discuss the intricate interactions between metastatic tumor cells and various resident and recruited cells. In addition, we emphasize the critical role of spatial remodeling of immune cells in liver metastasis. Finally, we review the recent advancements and the challenges faced in the clinical management of liver metastasis. Future precise antimetastatic treatments should fully consider individual heterogeneity and implement different targeted interventions based on stages of liver metastasis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, predominantly associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These infections drive persistent liver inflammation, culminating in cellular dysregulation, fibrosis, and cancer. Despite advancements in targeted therapies, drug resistance and the lack of reliable biomarkers for patient stratification still terribly hinder the treatment of viral HCC. To this end, the review delves into the intricate mechanisms underlying the malignant transformation of viral hepatitis to HCC, including viral integration, genomic instability, epigenetic modifications, oxidative stress, gut microbiota dysbiosis, chronic inflammation, immune escape, and abnormal signaling pathways, highlighting their complex interactions and synergies. Cutting-edge preclinical and clinical advancements in HCC management, including lifestyle modifications, drug therapies, immunotherapies, gene-based approaches, and innovative treatments, are further investigated, with particular priority given to their therapeutic potential and future applications in overcoming current limitations. By synthesizing recent scientific and clinical insights, this review aims to deepen the understanding of HCC pathogenesis in the context of chronic viral hepatitis, paving the way for novel therapeutic targets and personalized treatment strategies, ultimately improving patient outcomes.

Ultrasound-derived fat fraction (UDFF) is designed to assess the hepatic fat content quantitatively. A multicenter study that verifies the diagnostic performance of UDFF for detecting hepatic steatosis has not yet been reported. This study aimed to evaluate the performance of UDFF for diagnosing and grading hepatic steatosis. Participants referred for assessment of hepatic steatosis were prospectively recruited from eight hospitals. All participants underwent UDFF and magnetic resonance imaging proton density fat fraction (MRI-PDFF) examinations. MRI-PDFF was used as the reference for diagnosing hepatic steatosis. From January 2023 to July 2023, a total of 300 participants were included. The median body mass index was 25.4 kg/m² (interquartile range: 22.7–28.1). UDFF values were positively correlated with MRI-PDFF (R = 0.80, p < 0.001). Using MRI-PDFF ≥ 5%, ≥ 15%, and ≥ 25% as the reference standard for detecting mild, moderate, and severe hepatic steatosis, the best cutoff values of UDFF were 7.6% (area under the receiver operating characteristic curves [AUC] = 0.90), 15.9% (AUC = 0.90), and 22.3% (AUC = 0.91), respectively. Thus, UDFF has excellent diagnostic performance in detecting and grading hepatic steatosis.

This multicenter study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy (ICI-Chemo group) versus chemotherapy alone (Chemo group) for patients with cancer of unknown primary (CUP) in the first-line setting. We included patients with unfavorable CUP across four medical centers in China. Between January 2014 and December 2023, 117 patients were enrolled: 46 patients in the ICI-Chemo group and 71 patients in the Chemo group. After a median follow-up of 28.1 months, the ICI-Chemo group exhibited a significant improvement over the Chemo group in median PFS (9.10 months vs. 6.37 months; hazard ratio [HR] 0.46; 95% CI: 0.30–0.71; p < 0.001) and OS (35.67 months vs. 10.2 months; HR 0.37; 95% CI: 0.22–0.64; p < 0.001). Similarly, among patients who received TP (taxane plus platinum)-based chemotherapies, OS and PFS benefits were observed in the ICI-Chemo group. The objective response rate was higher in the ICI-Chemo group than in the Chemo group (54.35% vs. 22.53%, p < 0.001). Grade 3 or higher drug-related adverse events occurred in 11 patients (23.91%) in the ICI-Chemo group and 28 patients (39.44%) in the Chemo group. Thus, PD-1/PD-L1 inhibitors plus chemotherapy could be the preferred first-line treatment for patients with unfavorable CUP, providing improved efficacy and manageable toxicity.

Hyperactivation of fatty acid biosynthesis holds promise as a targeted therapeutic strategy in prostate cancer (PCa). However, inhibiting these enzymes could potentially promote metastatic progression in various other cancers. Herein, we found that depletion of acetyl-CoA carboxylase 1 (encoded by ACACA), the enzyme responsible for the first and rate-limiting step of de novo fatty acid biosynthesis, facilitated epithelial-mesenchymal transition (EMT) and migration of PCa cells. This finding was validated in vitro through cell migration assays and in vivo using a metastatic model established by tail vein injection of ACACA-depleted cells into BALB/c nude mice. Additionally, depletion of ACACA activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinases (ERK) pathway. Inhibition of the MAPK/ERK signaling pathway reduced EMT and migration in ACACA-depleted cells. Our study is the first to indicate targeting ACACA induces an “unexpected” escape program through activation of the MAPK/ERK signaling pathway in PCa, ultimately leading to EMT and metastasis. Therefore, we strongly recommend that the potential adverse effects of targeting ACACA or its derived therapeutic agents must be given extreme attention, especially in MAPK-related cancers.

Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.

Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP’s role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein’s pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.

Benign prostatic hyperplasia (BPH) is a prevalent disorder in aging males. It is investigated whether heat shock protein family A member 1A (HSPA1A), a cytoprotective chaperone induced under stress, has been implicated in the development of BPH. RNA-sequencing and single-cell sequencing analyses revealed significant upregulation of HSPA1A in BPH compared to controls. In vitro experiments elucidated that HSPA1A was localized in prostatic epithelium and stroma, with upregulated expression in BPH tissues. Moreover, HSPA1A silencing augmented apoptosis and reactive oxygen species (ROS) accumulation, inhibiting proliferation via ERK/JNK activation, while overexpression reversed these effects in prostatic BPH-1 and WPMY-1 cells. Additionally, ERK1/2 suppression with U0126 rescued the effects of HSPA1A silencing. In vivo, testosterone-induced BPH (T-BPH) rat models treated with the HSPA1A antagonist KNK437 exhibited prostatic atrophy and molecular changes consistent with reduced HSPA1A activity. Finally, we conducted a tissue microarray (TMA) analysis of 139 BPH specimens from Zhongnan Hospital of Wuhan University, which revealed a positive correlation between HSPA1A expression and clinical parameters, including prostate volume (PV), tPSA, fPSA, and IPSS. In conclusion, our findings suggested that HSPA1A attenuated apoptosis and oxidative stress through the ERK/JNK signaling pathway, contributing to BPH pathogenesis.

Sleep disorder significantly disrupts the quality of life for patients. Although it is clinically acknowledged, the fundamental neuropathological mechanisms are still not understood. Recent preclinical research has been directed toward understanding the fundamental mechanisms underlying the sleep deprivation and sleep/wake dysregulation. Sleep disorder is linked to changes in the structure and function of the neural basis of cognition. We reviewed the neural circuits related to sleep disorders, along with alterations in connectivity and brain region functions, based on advancements in electrophysiology and optogenetic/chemogenetic techniques. We subsequently outline the cellular and molecular modifications linked to sleep disorders in preclinical studies, primarily involving changes in neuronal metabolism, electrophysiological activity, synaptic plasticity, and glial cells. Correspondingly, on the basis of the crosstalk between the brain and peripheral organs, we elucidate the underlying mechanisms of the involvement of celiac disease and hepatic disease in the pathogenesis of sleep disorders. In this review, we mainly discussed the pathogenesis at molecular, cellular, and neural circuit levels that contribute to sleep disorder. The review also covered potential strategies for treating sleep disorders and future research avenues.

CD8+ tissue-resident memory T cells (TRM) are strategically located in peripheral tissues, enabling a rapid response to local infections, which is different from circulating memory CD8+ T cells. Their unique positioning makes them promising targets for vaccines designed to enhance protection at barrier sites and other organs. Recent studies have shown a correlation between CD8+ TRM cells and favorable clinical outcomes in various types of cancer, indicating their potential role in immune checkpoint blockade (ICB) therapies. However, the dual nature of CD8+ TRM cells presents challenges, as their inappropriate activation may lead to autoimmunity and chronic inflammatory conditions. This review highlights significant advancements in the field, focusing on the differentiation pathways and phenotypic heterogeneity of CD8+ TRM cells across different tissues and disease states. We also review their protective roles in various contexts and the implications for vaccine development against infections and treatment strategies for tumors. Overall, this comprehensive review outlines the common features of CD8+ TRM cell differentiation and biological functions, emphasizing their specific characteristics across diverse tissues and disease states, which can guide the design of therapies against infections and tumors while minimizing the risk of autoimmune diseases.

Pulmonary hypertension (PH) stands as a tumor paradigm cardiovascular disease marked by hyperproliferation of cells and vascular remodeling, culminating in heart failure. Complex genetic and epigenetic mechanisms collectively contribute to the disruption of pulmonary vascular homeostasis. In recent years, advancements in research technology have identified numerous gene deletions and mutations, in addition to bone morphogenetic protein receptor type 2, that are closely associated with the vascular remodeling process in PH. Additionally, epigenetic modifications such as RNA methylation, DNA methylation, histone modification, and noncoding RNAs have been shown to precisely regulate PH molecular networks in a cell-type-specific manner, emerging as potential biomarkers and therapeutic targets. This review summarizes and analyzes the roles and molecular mechanisms of currently identified genes and epigenetic factors in PH, emphasizing the pivotal role of long ncRNAs in its regulation. Additionally, it examines current clinical and preclinical therapies for PH targeting these genes and epigenetic factors and explores potential new treatment strategies.

Epigenetic regulation in disease development has been witnessed within this decade. RNA methylation is the predominant form of epigenetic regulation, and the most prevalent modification in RNA is N6-methyladenosine (m⁶A). Recently, RNA modification has emerged as a potential target for disease treatment. RNA modification is a posttranscriptional gene expression regulation that is involved in both physiological and pathological processes. Evidence suggests that m⁶A methylation significantly affects RNA metabolism, and its abnormal changes have been observed in a variety of diseases. Metabolic diseases are a series of diseases caused by abnormal metabolic processes of the body, the common metabolic diseases include diabetes mellitus, obesity, and nonalcoholic fatty liver disease, etc.; although the pathogenesis of these diseases differs from each other to the current understanding, most recent studies suggested pivotal role m⁶A in modulating these metabolic diseases, and m⁶A-based drug development has been on the agenda. This paper reviewed recent understanding of RNA modification in metabolic diseases, hoping to provide systematic information for those in this area.

Pancreatic ductal adenocarcinoma (PDAC) is highly susceptible to metastasis, making early detection of metastases and associated risk factors crucial for effective management. This study aimed to assess the performance of ¹⁸fluorine (¹⁸F)- fibroblast activation protein inhibitor-04 (¹⁸F-FAPI-04) positron emission tomography/computed tomography (PET/CT) in detecting metastasis and predicting pathological characteristics and risk factors in 67 PDAC patients. Comparisons were made with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT. Lesion identifications and radiotracer uptakes were evaluated through visual inspection and semiquantitative analysis using the maximum standardized uptake value (SUVmax). We analyzed the risk factors for metastasis and observed that ¹⁸F-FAPI-04 identified more positive lesions and showed significantly higher SUVmax values than ¹⁸F-FDG in both primary tumors and metastases, leading to upstaging in several cases. In primary tumors, ¹⁸F-FAPI-04 was associated with higher levels of poorly differentiated PDAC, compared to those with moderately differentiated tumors. Notably, the SUVmax of 18F-FAPI-04 in primary tumors demonstrated a significant correlation with pathological differentiation and served as an independent prognostic factor for peritoneal metastasis, rather than lymph node or liver metastasis. Our findings suggested that ¹⁸F-FAPI-04 PET/CT offers superior tumor detectability and improved node-metastasis (NM) staging in PDAC patients, positioning it as a more effective tool than ¹⁸F-FDG PET/CT.

Gut microbiota and integrins are known to contribute to colorectal cancer (CRC), but whether they interact has been unclear. Here, we provided evidence that Fusobacterium nucleatum upregulated integrin α5 (ITGA5) in CRC in both human patients and murine models. Knocking down ITGA5 in CRC cells weakened the ability of F. nucleatum to stimulate their malignant characteristics. Fusobacterium nucleatum increased intracellular Ca²⁺ concentration, which in turn promoted interaction between E-cadherin and Krüppel-like factor 4 (KLF4), resulting in KLF4 phosphorylation and translocation in the nucleus, where it induced ITGA5 transcription and activated the downstream signaling. Knocking down E-cadherin or chelating Ca²⁺ with BAPTA-AM antagonized the impact of F. nucleatum on KLF4, whereas knocking down KLF4 or chelating Ca²⁺ antagonized the bacteria’s oncogenic role. Knocking down KLF4 or ITGA5 attenuated F. nucleatum–induced growth of patient-derived organoids, subcutaneous xenografts, and orthotopic tumors, as well as liver metastasis in nude mice. Integrin α5 antibody antagonized the oncogenic role of F. nucleatum in vitro and in vivo. These findings suggest that F. nucleatum promotes the growth and metastasis of CRC by activating E-cadherin/KLF4/integrin α5 signaling in a Ca²⁺-dependent manner.

Metabolic dysfunction–associated steatohepatitis (MASH) has become one of the most common progressive liver diseases worldwide, but effective treatment options are severely unmet. Carabrone, a sesquiterpene lactone from the traditional Chinese herb Carpesium abrotanoides L., shows various pharmacological properties, whereas its effect on the improvement of MASH and the underlying mechanisms have not yet been reported. In this work, we revealed for the first time the beneficial effect of carabrone on MASH, including reducing liver lipid accumulation, inflammatory cell infiltration, and fibrosis in multiple diet-induced mice. Carabrone also alleviated lipid accumulation and inflammation in palmitic acid/oleic acid–stimulated hepatocytes. Mechanically, we identified signal transducers and transcriptional activator 3 (STAT3) as a key target of carabrone for treating MASH through quantitative chemical proteomic analysis, as well as the verification by the overexpression of STAT3 in vivo and in vitro. Further studies demonstrated that carabrone blocks MASH progression by inhibiting the activation of STAT3. More importantly, a new carabrone derivative CA-21 with stronger anti-MASH activity and affinity for STAT3 was discovered through rational structural modification. Taken together, our findings suggest that carabrone and CA-21 could be developed as promising drug candidates for MASH treatment.