Koala populations in Australia face a barrage of threats, chiefly, habitat degradation and the effects of climate change including drought and bushfire. Further, high rates of chlamydiosis, linked to koala retrovirus (KoRV) viral load, is a major contributing factor to northern population decline. However, recent work by Yu et al., (Cell, 2024) has provided a glimmer of hope: some koalas have evolved ‘adaptive genome immunity’, which is able to actively suppress endogenous KoRV transcription. A single KoRV-A provirus insertion within MAP4K4 gene's 3’ UTR is shown to be the trigger for production of sense and anti-sense piRNAs, and that MAP4K4 KoRV integration is linked to both a 20% reduction in proviral genome integrations and 10-fold reduction of KoRV transcription within male germline tissue. Here we discuss how this finding offers the potential to reduce koala disease burden and can be incorporated into conservation management to help save this iconic species.

Pancreatic cancer (PC) is an extremely deadly type of cancer, and the 5-year survival rate remains less than 10%. The tumour microenvironment (TME) affects the occurrence, progression and treatment outcomes of PC. MicroRNAs (miRNAs) are essential to regulate PC TME. This review delves into the different roles of miRNAs in the PC TME, including exosome communication, angiogenesis, interactions with cancer-associated fibroblasts, the immunological and neuronal microenvironments and metabolic reprogramming. However, research on the complex regulatory networks and synergistic effects of miRNAs in the TME is still insufficient, and their clinical translation and application face challenges. This review summarised the activities of miRNAs in the PC TME, guiding future research and therapeutic strategies involving miRNAs in PC. Future studies should integrate advanced technologies to decode the spatiotemporal dynamics of miRNA regulation within the TME and develop optimised nanodelivery systems for stable and targeted miRNA delivery, advancing clinical applications in PC treatment.

Rationale: Interleukin-11 (IL-11) has emerged as a significant player in tumourigenesis, with implications across various cancer types. However, its specific role in driving tumour progression in lung adenocarcinoma (LUAD) remains elusive. IL-11's multifaceted impact on both tumour cells and the tumour microenvironment underscores its potential as a therapeutic target in LUAD. This study aims to unravel the involvement of IL-11 in LUAD progression and its influence on the tumour microenvironment.

Methods: Here, we used transcriptomic and digital spatial profiling analyses together with clinic data from two retrospective LUAD patient cohorts. LUAD cell lines genetically engineered to overexpress or to silence IL-11 or its receptor (IL-11RA) were used for in vitro functional analysis and for in vivo experiments. Additionally, we used three different in vivo models: patient-derived xenografts (PDXs), tobacco-exposed mice and genetically engineered mouse models. A neutralising monoclonal antibody against IL-11RA was produced and tested.

Results: Our findings revealed a pivotal role for IL-11 in driving tumourigenesis across various mouse models, highlighting its capacity to modulate tumour immunity towards an immunosuppressive microenvironment. Moreover, we observed a correlation between IL-11 expression and poorer patient outcomes in LUAD. Notably, therapeutic targeting of IL-11RA with a neutralising antibody demonstrated significant anti-tumour efficacy in a PDX model.

Conclusion: The IL-11/IL-11RA axis emerges as a critical driver of LUAD tumourigenesis, exerting its effects through enhanced tumour cell proliferation and remodelling of the tumour microenvironment. Our study highlights the therapeutic potential of disrupting this axis, suggesting that patients exhibiting elevated IL-11 levels may benefit from therapies targeting the IL-11/IL-11RA pathway.

Background: The clinical guideline classifies T-LBL and T-ALL jointly, differentiating them merely by the bone marrow blast cell proportion. However, their distinct clinical manifestations, genetic profiles, and specific pathogenic requirements have prompted us to reevaluate the differences between them.

Methods and Results: We established the NCH-TALL-LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T-LBL samples and implemented single-cell RNA sequencing and single-cell T-cell receptor sequencing. Combining the single-cell RNA sequencing data of T-ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T-LBL are predominantly in the DN- and DP-stage blocking modes (DP cells dominate). This block mode in T-LBL generates signals that drive the development of an immunosuppressive microenvironment and the mediastinum preference. Additionally, E2F2, an active transcription factor in the DP and DN stages, upregulates the expression of UHRF1, resulting in hypermethylation of tumor suppressor genes. Findings from in vivo and in vitro research clearly show that demethylation therapy targeting this mechanism effectively inhibits tumor proliferation in T-LBL.

Conclusion: From the perspective of differentiation blockage, T-LBL and T-ALL represent different stages of the same disease, and the stage block bias of T-cell contributes to their heterogeneity.

Background: N6-methyladenosine (m6A) and alternative polyadenylation (APA) are common posttranscriptional regulatory mechanisms in eukaryotes. However, the m6A-dependent mechanism of APA regulation in ovarian cancer (OC) is still unclear.

Methods: The correlation between m6A and APA was analyzed by using RNA methylation sequencing of OC cells and single-cell sequencing of clinical samples from public databases. To explore the core regulatory factors that served as a bridge between m6A and APA, we employed RNA pull-down with biotin-labelled m6A, immunoprecipitation, mass spectrometry, western blot, protein purification and GST pull-down assays. Furthermore, the important target genes were screened by PAS-seq, eCLIP-seq, RIP-seq and meRIP-seq, and verified by RT-qPCR, 3′RACE, RNA stability, and dual luciferase reporter assays. Multiple phenotypic experiments were conducted to evaluate the function of the IGF2BP2-PUM2 axis in vitro and in vivo.

Results: This study found that the m6A was correlated with the APA and affected the 3′end processing in OC. The APA regulator CPSF6 tended to bind the m6A-modified transcripts in OC cells. Mechanistically, we demonstrated that the m6A reader IGF2BP2 KH1-4 domains could directly bind to the CPSF6-RS domain to regulate the 3′end processing of OC. Furthermore, sequencing revealed that the m6A was highly enriched in the 3′UTR near the proximal polyadenylation signal (PAS), which promotes the use of proximal PAS and leads to 3′UTR shortening. PUM2 was carried m6A and recognized by IGF2BP2, and CPSF6 was recruited at the proximal polyadenylation signal (pPAS) to generate the short-3′UTR transcript. The short PUM2 transcript was more stable than the long transcript, which promoted the malignant progression of OC.

Conclusions: We revealed a novel mechanism in which the m6A could regulate the APA processing of pre-mRNAs by crosstalk of IGF2BP2 and CPSF6. This study provides a potential strategy for the effective treatment of OC.

Introduction: Alzheimer's disease (AD) lacks a less invasive and early detectable biomarker. Here, we investigated the biomarker potential of miR-501-3p and miR-502-3p using different AD sources.

Methods: MiR-501-3p and miR-502-3p expressions were evaluated in AD cerebrospinal fluid (CSF) exosomes, serum exosomes, familial and sporadic AD fibroblasts and B-lymphocytes by qRT-PCR analysis. Further, miR-501-3p and miR-502-3p expressions were analysed in APP, Tau plasmid transfected cells media exosomes and in different brain cell types.

Results: MiR-501-3p and miR-502-3p expressions were significantly up-regulated in AD CSF exosomes relative to controls. MiRNA levels were high in accordance with amyloid plaque and NFT density in multiple brain regions. Similarly, both miRNAs were elevated in AD and MCI serum exosomes compared with controls. MiR-502-3p expression was high in familial AD and sporadic AD B-lymphocytes. MiR-501-3p and miR-502-3p expression were elevated intracellularly and secreted extracellularly in response to APP and Tau pathology. Finally, neurons and astrocytes displayed high expression of these miRNAs.

Discussion: These results suggest that miR-501-3p and miR-502-3p could be promising biomarkers for AD.

Lung cancer remains one of the leading causes of cancer-related deaths worldwide, and a growing body of evidence suggests that RNA modifications, including methylation, play a critical role in its progression. In this study, we investigated the role of the RNA demethylase fat mass and obesity-associated protein (FTO) in lung cancer progression and determined the underlying molecular mechanisms. FTO expression was significantly upregulated in LUAD and correlated with poor prognosis. FTO knockdown in lung patient-derived organoids and LUAD cell lines reduced their proliferation, invasion, and migration, and FTO knockdown in a Kras^G12D mouse model reduced the growth of lung tumours. Mechanistically, FTO demethylated m⁶A sites in the insulin-like growth factor-binding protein 3 (IGFBP3) 3′UTR, preventing IMP3 binding. The ribonuclear protein IMP3 was identified as a crucial functional reader that interacted with m⁶A-modified sites in the IGFBP3 3′UTR, thereby promoting IGFBP3 mRNA localisation to P-bodies and suppressing its translation. Elevated IGFBP3 activated AKT signalling and promoted tumour progression. Collectively, we revealed that FTO drives lung cancer progression via m⁶A-dependent sequestration of IGFBP3 mRNA into P-bodies by IMP3, which suppresses translation and activates AKT signalling. The FTO–IGFBP3–AKT axis thus represents a promising therapeutic target.

Background: Mutations in the AT-rich interactive domain-containing protein 1A (ARID1A) gene are frequently found in pancreatic cancer. However, the contribution of ARID1A inactivation to pancreatic tumorigenesis remains unclear. Previous work showed that depletion of Arid1a at early developmental stages induces metabolic disturbance and diabetes mellitus in mice.

Methods and Results: In this study, we generated a genetically engineered mouse model harboring both K-ras mutation and Arid1a depletion (KAR mice). We found that the combination of these two genetic alterations induces pancreatic tumor formation. Compared to tumors in K-ras and Tp53-mutant mice (KPC mice), KAR tumors showed increased immune cell infiltration and reduced stromal activation. Transcriptomic analysis revealed significant upregulation of fatty acid metabolism and fatty acid synthase (FASN) in KAR tumors, with ARID1A directly regulating Fasn expression. Pharmacological inhibition of FASN reduced tumor cell viability and slowed tumor progression in vivo. Analysis of clinical datasets showed an inverse correlation between ARID1A and FASN expression, with high FASN levels predicting worse patient survival.

Conclusion: ARID1A deficiency promotes fatty acid metabolism to accelerate pancreatic tumorigenesis. FASN is a potential therapeutic target for ARID1A-deficient pancreatic cancer.Mutations in AT-rich interactive domain-containing protein 1A (ARID1A) gene are frequently found in pancreatic cancer. However, the contribution of ARID1A inactivation to pancreatic tumourigenesis is not well-characterised. Previously, we generated genetically engineered mice with specific depletion of Arid1a gene in the pancreas and found that depletion of Arid1a at early developmental stage induced metabolic disturbance and diabetes mellitus. In this study, we established a mouse model with K-ras mutation and Arid1a depletion (KAR mice) in the pancreas and showed that the combination of these two genetic alterations induced pancreatic tumour formation. Compared to the tumours developed in mice with K-ras mutation and Tp53 deficiency (KPC mice), KAR tumours exhibited increased immune cell infiltration and reduced stromal activation. Our results demonstrated a significant upregulation of fatty acid metabolism and fatty acid synthase (FASN) in the KAR tumours, with ARID1A directly regulating FASN expression. Inhibition of FASN by chemical inhibitor reduced tumour cell viability and slowed tumour progression in mice. Clinical data revealed a negative correlation between ARID1A expression and FASN, with high FASN levels associated with worse patient survival. Collectively, ARID1A deficiency upregulates fatty acid metabolism to accelerate pancreatic tumourigenesis and FASN is a potential therapeutic target for ARID1A-deficient pancreatic cancer.

Cancer therapy resistance (CTR) remains a significant challenge in oncology. Traditional methods like imaging, liquid biopsies and conventional omics analyses provide valuable insights, but lack the spatial resolution to fully characterise heterogeneity of tumour and the tumour microenvironment (TME). Recent advancements in spatial omics technologies offer unprecedented insights into the spatial organisation of tumours and TME. In this review, we summarise current methodologies for CTR research and highlight how spatial omics technologies and computational methods are revolutionising our understanding of CTR mechanisms. We also summarise recent studies leveraging spatial omics to uncover novel insights into CTR across various cancer types and therapies and discuss future opportunities.

CD70, which is a ligand belonging to tumour necrosis factors, exhibits aberrant overexpression among multiple hematologic and solid malignancies and has drawn extensive research enthusiasm as a target to treat and diagnose cancers. CD70-targeted immuno-PET/CT is an emerging approach for cancer diagnosis, with the potential to improve tumour detection, assist disease staging, and monitor therapeutic response. CD70-targeted therapeutic approaches, involving antibody–drug conjugates, CAR-T, CAR-NK, and monoclonal antibodies, have shown encouraging activity in preclinical models and preliminary signals of efficacy in early clinical studies. In addition to these monotherapies, increasing efforts have focused on rational combination strategies that aim to enhance antitumor efficacy, reverse immune suppression, and overcome resistance. This review comprehensively summarizes the diagnostic and therapeutic advances in CD70-targeted strategies, discusses ongoing barriers, and outlines future directions to advance CD70-targeted imaging and therapeutic strategies through mechanistic research and clinical translation.

Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post-translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC-targeted interventions in cancer immunotherapy.

Background: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual—extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles—respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.

Methods: We used a mouse model for mitochondrial myopathy (“deletor”), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.

Results: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.

Conclusions: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Cancer stem cells (CSCs) are a core subpopulation of tumour tissues exhibiting stem cell properties. Although they constitute only a minority of tumour cells, CSCs have become a central force driving tumourigenesis, metastasis, recurrence and resistance to therapy, owing to their abilities for self-renewal, multi-lineage differentiation and tumour-initiating ability. Recent advances in multi-omics analysis, lineage tracing and single-cell sequencing technologies have systematically elucidated the dynamic biology of CSCs, including their epigenetic plasticity, metabolic adaptations and phenotypic heterogeneity, which depend on their ecological niche. In this review, we summarise the biological properties of CSCs, the molecular regulatory mechanisms and the complex interactions with the tumour microenvironment. We focus on strategies to target CSCs and the clinical translational challenges associated with these approaches. Collectively, this review organically integrates basic mechanisms and clinical translational research on CSCs, offering a comprehensive framework for understanding tumour biology and developing precision therapeutic strategies.

Background: Osteoblast senescence is a central driverof age-related osteoporosis. Accumulating evidence shows that counteractingthis senescence can substantially mitigate bone loss. In this review, we summarize the hallmarks of osteoblast senescence, the signaling pathways involved, and therapeutic strategies that target osteoblast senescence tocombat age-related osteoporosis.

Methods: Chronic diseases associated with ageingpose a significant threat to human health. Studies have shown that osteoporosisis closely linked to the ageing process of the body and the senescence ofosteoblasts within the bone microenvironment. Counteracting the senescence ofosteoblasts and maintaining the balance of differentiation, proliferation andfunction between osteoclasts and osteoblasts has been a key focus in the research of age-related osteoporosis and bone loss. The biological behaviour andfunctionality of the osteoblast lineage related to senescence are modulated bya variety of targets, including signalling pathways, proteins and genes associated with ageing. This review aims to discuss the senescence-related characteristics of the osteoblast lineage, dissect the interplay and mechanisms between it and ageing-associated signalling pathways, proteinsand genes, as well as current strategies for the prevention and treatment ofosteoblast senescence.

Conclusion: This review systematically examines the regulatory interactions among markers, therapeutic targets, and signalingpathways associated with osteoblast senescence, alongside current potential strategies for targeting this process. It provides more comprehensive information for future research into the complex mechanisms underlying age-related osteoporosis driven by osteoblast senescence.

Background: Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.

Methods: Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1^−/- and ACOD1^fl/flLysM^cre NEC mouse models.

Results: We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.

Conclusions: Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.

Background: Parkinson's disease (PD) is a common neurodegenerative movement disorder, mainly characterized by the degeneration and loss of dopaminergic neurons in the substantia nigra. Oxidative stress is considered to be a key contributor to dopaminergic neuronal degeneration, triggering a series of downstream events such as mitochondrial dysfunction, neuroinflammation and misfolded protein aggregation, which ultimately exacerbate the development of PD. Deubiquitinating enzymes (DUBs) regulate oxidative stress, but their roles in PD remain unclear.

Methods: GEO database analysis and western blotting were used to analyze the expression of YOD1in PD patients and PD mouse models. Genetic knockout (KO) of YOD1 was performed to assess its effects in PD pathogenesis. The substance of YOD1 was measured via co-immunoprecipitation (Co-IP) coupled with LC-MS/MS analysis. Then the effect of YOD1-mediated motor deficits and oxidative damage were investigated using open field test, swimming test, pole test, immunofluorescence (IF) and cellular analyses.

Results: YOD1 was highly expressed in PD patients and 6-OHDA-induced PD model mice and mediated reactive oxygen species (ROS) production. YOD1 KO ameliorated motor impairments and oxidative stress in PD model mice. YOD1 directly bound PKM2 and reduces its ubiquitination level by removing the K63-linked ubiquitin chain of PKM2, thereby increasing the tetramer level and reducing the dimer level of PKM2. It then inhibited dimerized PKM2 entry into the nucleus and regulated Nrf2-mediated antioxidant responses, but YOD1 does not change the stability of PKM2 protein.

Conclusions: Our study identifies YOD1 as a oxidative-sensitive regulator of PD progression, operating via the YOD1-PKM2-Nrf2 axis. Targeting YOD1 may offer a novel therapeutic strategy for PD.

High-grade serous ovarian carcinoma (HGSC) is a lethal malignancy characterized by high incidence, mortality, and chemoresistance. However, its molecular drivers are unknown. In this study, spatially resolved proteomics was applied to 1144 formalin-fixed paraffin-embedded tissue spots obtained by laser capture microdissection from 10 patients with HGSC and divergent carboplatin-paclitaxel (CP) responses. Specific sampling revealed stroma-driven tumour heterogeneity, identifying 642 tumour-specific and 180 stroma-specific proteins, with 505 CP-responsive therapeutic targets. Most of these protein signatures represented previously unreported associations with chemoresistance in HGSCs. Two clinically significant spatial proteomic maps were generated by introducing tumour (TS) and chemical (CS) scores. TS analysis revealed conserved tissue architecture across CP response groups, whereas CS mapping revealed pretreatment metabolic reprogramming (rather than proliferation) as the defining feature of chemo-resistant tumours, challenging current resistance paradigms. Immunohistochemical validation of HGSC tissue microarrays confirmed the spatial proteomic localization of TFRC and PDLIM3, which are linked to tumour progression, while establishing their novel role as chemotherapy resistance biomarkers through this study, with broader predictive potential observed across additional targets in the discovery cohort. This study developed a spatially resolved proteomic framework to enhance the diagnostic and therapeutic strategies for HGSC.