Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent extranodal marginal B-cell lymphoma that can occur at any age and is generally less aggressive, with a favorable prognosis. However, due to the low incidence of gastric MALT, current research mainly focuses on case reports and retrospective analyses of small samples, and there is a lack of large sample data and systematic reviews, which leads to difficulties in diagnosis and delays in treatment. In addition, some patients can transform into more aggressive diffuse large B-cell lymphoma, which in turn affects the survival and prognosis of patients. In this review, we summarized the epidemiology, etiology, treatment methods and prognosis of gastric MALT lymphoma, with the aim of enhancing understanding of its diagnosis and treatment and improving treatment outcomes and patients' quality of life.

Response to: Limitations of the p16-3MR Mouse Model for Detecting and Eliminating Senescent Cells by Hori et al?

Scalar-mediated interactions may exist among neutrinos, dark matter particles, or between the two. Double β-decay experiments provide a powerful tool to probe such exotic interactions. Using ^{136}Xe double β-decay data from PandaX-4T, we perform the first direct spectral search in the energy range of 20 to 2800 keV, setting the most stringent limits to date on scalar-mediated neutrino self-interactions for mediator masses below 2  MeV/c^{2}. These results place significant constraints on models invoking such interactions to alleviate the Hubble tension. Assuming the same scalar also mediates dark matter self-interactions, constraints on the dark matter-scalar interactions can be placed in conjunction with cosmological constraints.

The p163MR mouse model has been widely used to visualize and conditionally eliminate p16 expressing senescent cells in vivo and has been applied across diverse biological contexts, including tissue repair, fibrosis, cancer, therapy response, and aging. Despite the development of multiple senescence reporter and ablation systems, p163MR stands out for its broad and sustained adoption across independent laboratories. Here, we review the extensive published literature supporting the reproducibility and utility of the p163MR system and present new validation data across acute and chronic senescence-inducing conditions. We demonstrate reproducible induction of p16 associated bioluminescence during wound healing, chemotherapy, and aging, as well as partial but consistent reduction following ganciclovir treatment. We further delineate the strengths and limitations of the individual components of the 3MR construct, including HSV thymidine kinase mediated clearance, Renilla luciferase based bioluminescence, and monomeric red fluorescent protein, and discuss how factors such as cell abundance, tissue context, pigmentation, and substrate chemistry influence detection sensitivity. Together, these data confirm that the p163MR model is a functional and versatile tool for studying senescent cells in vivo when used with appropriate experimental design and interpretation, and they provide support for its continued application alongside emerging senescence models. ### Competing Interest Statement M.D. is the founder and shareholder of Cleara Biotech and an advisor for Oisin Biotechnologies and Rubedo Life Sciences. The M.D. The laboratory received funding from Ono Pharmaceuticals. None of the aforementioned companies were involved in this study. The other authors have no conflicts of interest to declare.

Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of ALDH3A1 is transcriptionally governed by TP63, which binds to super-enhancer of ALDH3A1. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.

The use of the predatory mite Cheyletus malaccensis (Oudemans) for controlling stored grain pests represents an ecologically sustainable biocontrol strategy, while sulfuryl fluoride fumigation serves as an effective chemical control method. This study investigates the feasibility of combining C. malaccensis with sulfuryl fluoride fumigation to manage stored grain pests. Additionally, we employ transcriptomic analysis to elucidate the physiological and metabolic mechanisms that C. malaccensis engages under stress conditions. Under the same fumigation duration, the mortality rates of both adult and egg increased with higher concentrations of sulfuryl fluoride. The LC50 for adult mites after 48 h of fumigation was approximately 1.58 g/m3, while the LC50 for egg was around 26.48 g/m3. When the fumigation time for egg was extended to 60 h, the mortality rate at a concentration of 25 g/m3 increased by approximately 1.4 times; after 72 h, the mortality rate at 15 g/m3 rose by 3.6 times. Egg exhibited greater tolerance to sulfuryl fluoride fumigation compared to adult. Neither adult nor egg could survive in high-concentration, long-duration fumigation environments. C. malaccensis can be released after the fumigation has dissipated (with sulfuryl fluoride concentrations not exceeding 2.3 g/m3), allowing it to effectively establish populations in real storage facilities for long-term control. In the transcriptome data, a total of 4730 differentially expressed genes were identified, including 3489 upregulated and 1241 downregulated genes. Through GO and KEGG analysis, it was found that the pathways involved in lipid metabolism and energy metabolism processes, pathogen infection and immune response were significant.

Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors of cyclin-dependent kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast cancer growth by inducing a senescent-like state. However, the long-term treatment efficacy remains limited by the development of drug resistance, so clearance of senescent-like cancer cells may extend the durability of treatment. However, we show here that while CDK4/6i-treated breast cancer cells exhibit various senescence-associated phenotypes, they remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, we identify a significantly increased lysosomal mass and altered lysosomal structure across various breast cancer cell types upon exposure to CDK4/6i in preclinical systems and clinical specimens. We demonstrate that these CDK4/6i-induced lysosomal alterations render breast cancer cells sensitive to lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) and salinomycin. Importantly, sequential treatment with CDK4/6i and lysosomotropic agents effectively reduces the growth of both hormone receptor-positive (HR+) and subsets of triple-negative breast cancer (TNBC) cells in vivo. This sequential therapeutic strategy offers a promising approach to eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence and enhancing the overall efficacy of breast cancer therapy.

Endogenous retroviruses (ERVs), widely distributed in the human genome, are usually epigenetically silenced but can be reactivated in cancer. Activated ERVs may act as regulatory elements or produce noncoding RNAs that modulate gene expression and affect tumor biology. Their role in pancreatic ductal adenocarcinoma (PDAC), particularly in ferroptosis regulation, remains unclear. Here, we identify human endogenous retrovirus-H (HERVH) derived enhancer RNAs (eRNAs) aberrantly overexpressed in PDAC by integrating gene expression and histone modification data. Silencing HERVH markedly suppresses PDAC proliferation and tumor growth. Mechanistically, HERVH transcription is driven by the super-enhancer–associated transcription factor Krüppel-like factor 5 (KLF5), and HERVH eRNAs cooperate with KLF5 to transactivate a distal super-enhancer upstream of aldehyde dehydrogenase family 1 member 3 (ALDH1A3), increasing its expression. ALDH1A3 inhibits the reactive oxygen species/specificity protein 1/spermidine/spermine N1-acetyltransferase 1 (ROS/Sp1/SAT1) cascade, reducing lipid peroxidation and ferroptosis. Disrupting this axis induces ferroptotic death and impairs PDAC development. Our study reveals a previously unrecognized mechanism in which HERVH-derived eRNAs regulate ferroptosis via super-enhancer–mediated transcriptional reprogramming and highlights the KLF5/HERVH/ALDH1A3 pathway as a potential therapeutic target in PDAC.

Aging is marked by the accumulation of cells expressing the cyclin-dependent kinase inhibitor p16Ink4a. These p16⁺ cells, largely senescent, contribute to inflammation and tissue dysfunction. While eliminating p16⁺ cells improves healthspan, sex-specific differences in their burden and clearance remain unclear. Through combined transcriptomic, proteomic, and functional analyses, we reveal distinct sex-dependent dynamics of p16⁺ cells during aging. Female mice accumulate significantly more p16⁺ cells across multiple tissues, particularly in the liver. In the p16-3MR model, selective ablation of these cells enhances grip strength, promotes skin regeneration, and reduces liver damage exclusively in females. Multi-omics profiling shows that p16⁺ cell removal shifts female liver expression toward youthful, health-associated profiles, marked by improved mitochondrial activity and reduced inflammatory signaling-molecular patterns resembling those induced by longevity interventions such as calorie restriction, rapamycin, and acarbose. Integrative analysis of our and independent datasets identifies a conserved transcriptional network involving Srm, Cd36, and Lrrfip1, suggesting shared mitochondrial-immune regulatory mechanisms. Overall, our findings establish p16⁺ cells as critical yet heterogeneous drivers of tissue aging, uncover sex-specific differences in their abundance and senolytic responsiveness, and support the development of precision senotherapeutics that consider sex as a key biological variable in aging and rejuvenation.

Background: Glycoprotein non-metastatic melanoma B (GPNMB)/osteoactivin was first identified in the human melanoma cell lines. GPNMB plays a key role in the anti-inflammatory and antioxidative functions as well as osteoblast differentiation, cancer progression, and tissue regeneration. Recently, GPNMB was used as an anti-aging vaccine for mice. The present study aimed to investigate the potential of biofluid GPNMB as an aging biomarker in humans using serum and urine samples from an aging Chinese population. Methods: We analyzed RNA-sequencing data (GSE132040) from 17 murine organs across different ages to assess the gene expression of potential ageing biomarkers. Spearman's correlation coefficients were used to evaluate the relationship between gene expression and age. Meanwhile, a cross-sectional population study was conducted, which included 473 participants (aged 25-91 years), a representative subset of participants from the Peng Zu Study on Healthy Ageing in China (Peng Zu Cohort). Biofluid GPNMB levels were measured by ELISA. The associations of serum and urine GPNMB levels with various clinical and anthropometrical indices were assessed using ANOVA, Kruskal-Wallis H test, and univariate and multivariate linear regression analyses. Results: In mice, the Gpnmb mRNA expression levels showed a significant positive association with age in multiple organs in mice (P < 0.05). In Peng Zu Cohort, biofluid (both serum and urine) GPNMB levels showed a positive correlation with age (P < 0.05). Univariate linear regression analysis revealed that serum GPNMB levels were negatively associated with skeletal muscle mass index (SMI, P < 0.05) and insulin-like growth factor 1 (IGF-1, P < 0.05), and urine GPNMB levels showed a negative association with total bile acids (TBA, P < 0.05). Multivariate linear regression analysis further indicated that serum GPNMB levels negatively correlated with the systemic immune-inflammation index (SII, P < 0.05), and the urine GPNMB levels maintained a negative association with TBA (P < 0.05), additionally, urine GPNMB levels in men were significantly lower than in women (P < 0.05). Conclusions: The biofluid GPNMB was a strong clinical biomarker candidate for estimating biological aging.

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions. The senescence-associated secretory phenotype (SASP) mediates the tissue effects of senescent cells. This Review discusses the composition, regulation and various biological implications of the SASP and its uses as a biomarker and a target of senomorphic drugs to treat cancer and other age-related conditions.

Breast cancer remains a leading cause of mortality globally, emphasizing the need to develop more effective and well-tolerated treatments. Pharmacological inhibitors of Cyclin-Dependent Kinases (CDK) 4 and 6 (CDK4/6i) can inhibit breast cancer growth by inducing a senescent-like state. However, long-term treatment efficacy remains hindered by the development of drug resistance and restoration of cell proliferation. Thus, clearance of senescent-like cancer cells may extend the durability of treatment. In this study, we showed that CDK4/6i-treated breast cancer cells exhibit various senescence-associated phenotypes that remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, we identified a significantly increased lysosomal mass and altered lysosomal structure across various breast cancer cell types upon exposure to CDK4/6i in preclinical systems and clinical specimens. We demonstrated that these lysosomal alterations render breast cancer cells sensitive to lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) and salinomycin. Importantly, sequential treatment with CDK4/6i/lysosomotropic agents effectively reduced the growth of both Hormone Receptor-positive (HR+) and triple-negative breast cancer (TNBC) cells in vivo. This sequential therapeutic strategy offers a promising approach to eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence and enhancing the overall efficacy of breast cancer therapy. ### Competing Interest Statement M.D. is founder and shareholder of Cleara Biotech and an advisor for Oisin Biotechnologies and Rubedo Life Sciences. The M.D. laboratory receives funding from Ono Pharmaceuticals. None of the mentioned companies were involved in the study. The remaining authors declare no competing interests.

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

Supplementary Figures S1 - S10, Tables S1 - S2

The effect of aerobic glycolysis remains elusive in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of deubiquitination is involved in glycolysis, by targeting glycolytic rate-limiting enzymes. Here, we demonstrated that upregulated deubiquitinase ubiquitin-specific peptidase 1 (USP1) expression correlated with poor prognosis in pediatric primary T-ALL samples. USP1 depletion abolished cellular proliferation and attenuated glycolytic metabolism. In vivo experiments showed that USP1 suppression decreased leukemia progression in nude mice. Inhibition of USP1 caused a decrease in both mRNA and protein levels in lactate dehydrogenase A (LDHA), a critical glycolytic enzyme. Moreover, USP1 interacted with and deubiquitinated polo-like kinase 1 (PLK1), a critical regulator of glycolysis. Overexpression of USP1 with upregulated PLK1 was observed in most samples of patients with T-ALL. In addition, PLK1 inhibition reduced LDHA expression and abrogated the USP1-mediated increase of cell proliferation and lactate level. Ectopic expression of LDHA can rescue the suppressive effect of USP1 silencing on cell growth and lactate production. Pharmacological inhibition of USP1 by ML323 exhibited cell cytotoxicity in human T-ALL cells. Taken together, our results demonstrated that USP1 may be a promising therapeutic target in pediatric T-ALL.

Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.

Supplementary Figures S1-S5.

Amplification and overexpression of MCM7 in ESCC. A. Amplification of MCM7 in array CGH study. B. Validation of MCM7 amplification by FISH. Left: two MCM7 signals in peripheral blood cells; Middle: two MCM7 signals in ESCC cells; Right: more than four MCM7 signals in ESCC cells. C. MCM7 overexpressed in ESCC by semi-quantitative RT-PCR. D. MCM7 overexpressed in ESCC by Western blotting. E. MCM7 overexpressed in ESCC by IHC.

Individual identification and authentication techniques are merged into many aspects of human life with various applications, including access control, payment or banking transfer, and healthcare. Yet conventional identification and authentication methods such as passwords, biometrics, tokens, and smart cards suffer from inconvenience and/or insecurity. Here, inspired by quick response (QR) code and implantable microdevices, implantable and minimally-invasive QR code subcutaneous microchips (QRC-SMs) are proposed to be an effective approach to carry useful and private information, thus enabling individual identification and authentication. Two types of QRC-SMs, QRC-SMs with "hole" and "flat" elements and QRC-SMs with "titanium-coated" and "non-coated" elements, are designed and fabricated to store personal information. Corresponding ultrasound microscopy and photoacoustic microscopy are used for imaging the QR code pattern underneath skin, and open-source artificial intelligence algorithm is applied for QR code detection and recognition. Ex vivo experiments under tissue and in vivo experiments with QRC-SMs implanted in live mice have been performed, demonstrating successful information retrieval from implanted QRC-SMs. QRC-SMs are hidden subcutaneously and invisible to the eyes. They cannot be forgotten, misplaced or lost, and can always be ready for timely medical identification, access control, and payment or banking transfer. Hence, QRC-SMs provide promising routes towards private, secure, and convenient individual identification and authentication.