Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
DNA methylation-mediated downregulation of MEIS2 correlates with tumor development and progression in gastric cancer.
Zhang Y, Wu Y, Cao D … +5 more , Jia Z, Fu C, Yu X, Cao X, Jiang J
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42385864 · Publisher ↗
BACKGROUND: Gastric cancer (GC) is a molecularly heterogeneous disease with poor prognosis. DNA methylation plays a critical role in its pathogenesis, and Homeobox genes are known to be frequently dysregulated through ep...
BACKGROUND: Gastric cancer (GC) is a molecularly heterogeneous disease with poor prognosis. DNA methylation plays a critical role in its pathogenesis, and Homeobox genes are known to be frequently dysregulated through epigenetic mechanisms in various cancers. However, the role of the homeobox gene MEIS2 in GC remains unclear. METHOD: Integrated bioinformatics analysis of RNA-seq and DNA methylation data from TCGA and a K19-Wnt1/C2mE transgenic (Gan) mouse model identified MEIS2 as a candidate gene. Its clinical relevance was assessed using GEO datasets and a clinical cohort of 293 GC patients. Functional roles were investigated through in vitro assays, RNA-seq, and metabolic analyses. Methylation-specific PCR, MassARRAY, and ChIP were used to explore the regulatory mechanisms. RESULTS: MEIS2 was significantly downregulated in GC tissues, and its low expression was associated with advanced tumor stage, neural invasion, and poor overall survival. Functional experiments demonstrated that MEIS2 overexpression suppressed GC cell proliferation, migration, and invasion, induced apoptosis, and inhibited glycolysis by reducing glucose uptake, lactate production, and the expression of key glycolytic enzymes. Hypermethylation of the MEIS2 promoter region (-811 to -757 bp) was negatively correlated with its expression. DNMT1 was found to bind directly to this region and promote MEIS2 promoter hypermethylation, leading to its transcriptional downregulation. CONCLUSION: MEIS2 acts as a tumor suppressor in GC, and its downregulation is mediated by DNMT1-driven promoter hypermethylation. These findings highlight MEIS2 as a potential therapeutic target and prognostic biomarker in GC.
A proliferation-inducing ligand enhances the anti-tumor effect of BCMA CAR T-cell through inhibition of soluble BCMA.
She H, Lin J, Zhou D … +7 more , Zhang X, Zheng F, Feng Q, Xiao L, Chen W, Yan Z, Pan B
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42385863 · Publisher ↗
A proliferation-inducing ligand (APRIL), a ligand of B-cell maturation antigen (BCMA), might have an impact on the efficacy of BCMA CAR T-cell in multiple myeloma. Here, we found plasma concentrations of APRIL increased...
A proliferation-inducing ligand (APRIL), a ligand of B-cell maturation antigen (BCMA), might have an impact on the efficacy of BCMA CAR T-cell in multiple myeloma. Here, we found plasma concentrations of APRIL increased (> 1 nM) during the first month in patients showing responses to BCMA CAR T-cell therapies, and APRIL levels negatively correlated with soluble BCMA (sBCMA) levels. APRIL bound with sBCMA and decreased the detectability of sBCMA in ELISA detection, an effect different from γ-secretase inhibitor. APRIL also bound cell membrane BCMA but with a much lower affinity comparing with sBCMA. sBCMA bound with BCMA CAR T-cell, and decreased the binding and killing of myeloma cells by BCMA CAR T-cells in vitro. APRIL, at concentrations of 2 and 10 nM, inhibited the binding of sBCMA and BCMA CAR T-cell, and increased the binding and killing of myeloma cells by BCMA CAR T-cells. In murine xenotransplant myeloma models, giving APRIL during the first week after infusion of BCMA CAR T-cells increased IFNγ-positive CAR T-cells in the tumor tissues, and enhanced the anti-tumor effect of CAR T-cell. In conclusion, APRIL counteracted the actions of sBCMA in BCMA CAR T-cell-mediated binding and killing of myeloma cells which might contribute to the efficacy of BCMA CAR T-cell therapies.
Emerging roles of SIRT7 in metabolic homeostasis and related disorders.
Yu S, Rabiu L, Zhu WG … +1 more , Tian Y
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42385862 · Publisher ↗
Metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic dysfunction-associated steatotic liver disease, are major global health challenges, sharing features such as disrupted glucose-lipid homeosta...
Metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic dysfunction-associated steatotic liver disease, are major global health challenges, sharing features such as disrupted glucose-lipid homeostasis, mitochondrial dysfunction, and chronic low-grade inflammation. Among mammalian sirtuins, SIRT7, though poorly characterized, is important for chromatin state, metabolic flux, mitochondrial function, and inflammatory responses in metabolically active tissues. Clinical and preclinical studies link dysregulated SIRT7 to multiple metabolic diseases, with tissue-specific effects on hepatic lipogenesis, insulin signaling, adipose function, and even metabolism-related hepatocellular carcinoma. Despite advances in the development of SIRT7-targeted inhibitors, significant challenges remain, including the absence of selective activators, limited structural characterization, incomplete understanding of tissue-specific regulatory mechanisms, and potential dose-dependent effects. This review integrates current knowledge on SIRT7-mediated regulatory networks and discusses emerging efforts to develop selective SIRT7 modulators, including structural-guided approaches based on AlphaFold models.
Baicalein mitigates anti-tuberculosis-induced liver injury via inhibition of lipid peroxidation mediated by ferritinophagy and ferroptosis: Involvement of Yap 1/NCOA4 signaling.
Liu Y, Liu Z, Luo C … +6 more , Chen W, Xia Z, Zhou H, Huang J, You M, Yang G
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42385286 · Publisher ↗
Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a leading cause of impaired anti-TB treatment efficacy in patients with tuberculosis. Baicalein (Bai), a dietary flavonoid from the root of Scutellaria baicalensi...
Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a leading cause of impaired anti-TB treatment efficacy in patients with tuberculosis. Baicalein (Bai), a dietary flavonoid from the root of Scutellaria baicalensis, exhibits diverse therapeutic effects across a broad spectrum of diseases. This study aimed to investigate the protective effects of Bai against ATB-DILI and to elucidate the role of ferritinophagy, using an integrated approach combining network pharmacology, animal models, and cellular assays. Bai treatment ameliorated ATB-DILI and hepatocyte injury in vivo and in vitro, respectively. Reactive oxygen species production, lipid accumulation, and cellular ferroptosis caused by anti-TB drugs were ameliorated following Bai treatment both in vivo and in vitro. Furthermore, Bai treatment alleviated excessive ferritinophagy induced by anti-TB drugs by modulating the nuclear receptor coactivator 4 (NCOA4)/ferritin heavy chain 1 (FTH1) signaling pathway. Notably, knockdown of YES-associated protein 1 (YAP1) abrogated the protective effects of Bai treatment, preventing it from alleviating the anti-TB drug-induced increase in NCOA4 expression, decrease in FTH1 expression, iron overload, and subsequent ferroptosis and lipid peroxidation in rat liver and hepatocytes. This study suggested that Bai treatment attenuates anti-TB drug-induced hepatocyte injury via inhibition of ferritinophagy activation-induced ferroptosis, which is regulated through the YAP1/NCOA4/FTH1 signaling pathway. These findings establish a novel therapeutic target for Bai in the treatment of ATB-DILI and provide a rational basis for its clinical application.
Redefining first-line standards: The role of next-generation HER2-Targeted therapies in HER2-positive metastatic breast cancer.
Zhang L, Li H, Sun S … +4 more , Li N, Zhao S, Zhao Z, Li M
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42379327 · Publisher ↗
The combination of trastuzumab, pertuzumab, and taxane (THP) has been the cornerstone of the first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) since the CLE...
The combination of trastuzumab, pertuzumab, and taxane (THP) has been the cornerstone of the first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) since the CLEOPATRA trial. However, this long-standing paradigm is now being redefined by compelling evidence from practice-changing trials. Recent advances are challenging THP's dominance with impressive clinical activity across multiple trials evaluating anti-HER2 antibody-drug conjugates (ADC) and CDK4/6 inhibitors. The DESTINY-Breast09 (DB09) trial established superiority of the ADC trastuzumab deruxtecan (T-DXd) combined with pertuzumab over THP, positioning chemotherapy-free strategies as potential new standards. For patients with HR+/HER2+ disease, the PATINA study extends the first-line strategy by demonstrating that adding a CDK4/6 inhibitor as maintenance therapy significantly improves outcomes for patients with HR+/HER2+ disease who have completed initial THP induction. This review comprehensively summarizes the evolution of first-line treatment strategies for HER2+ mBC and critically evaluates clinical evidence from pivotal trials, including emerging evidence in first-line treatments and new agents with potential first-line applications. Challenges, including drug resistance mechanisms, optimal treatment sequencing, and management of special populations, are also discussed.
Organoid-based platforms for oncolytic virus discovery and optimization: Bridging in vitro innovation and clinical translation.
Yang F, Wang H, Wang Y
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42379326 · Publisher ↗
Although oncolytic virus therapy has shown promising efficacy in preclinical studies, its clinical translation remains limited because conventional experimental models fail to replicate the human tumor microenvironment a...
Although oncolytic virus therapy has shown promising efficacy in preclinical studies, its clinical translation remains limited because conventional experimental models fail to replicate the human tumor microenvironment accurately. As an advanced three-dimensional culture system, organoid technology provides a powerful platform to address this challenge, as it retains the heterogeneity and microenvironmental features of primary tumors. This review systematically summarizes organoid modeling technology and highlights its critical role in the research and development of oncolytic viruses. The development of organoid biobanks, together with their integration into high-throughput screening systems, has facilitated rational viral engineering and targeted optimization through large-scale data analysis. In clinical applications, patient-derived organoids have enabled personalized prediction of therapeutic responses by serving as functional models for drug testing. Despite ongoing challenges in protocol standardization and in accurately simulating the immune microenvironment, organoid technology is rapidly becoming a key bridge between basic research and clinical translation in oncolytic virotherapy, accelerating the development of next-generation oncolytic virus therapies.
Targeting transcriptional and post-transcriptional pathways in head and neck cancer.
Kumar P, Dey A, Lakhera R … +3 more , Maini J, Das BC, Gupta S
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42379325 · Publisher ↗
Head and neck cancer (HNC) is a molecularly heterogeneous group of multisite malignancies that arise through two major carcinogenic routes- first, chemical carcinogenesis associated with tobacco use and/or alcohol intake...
Head and neck cancer (HNC) is a molecularly heterogeneous group of multisite malignancies that arise through two major carcinogenic routes- first, chemical carcinogenesis associated with tobacco use and/or alcohol intake, and second, infection with oncogenic human papillomaviruses (HPVs) in a clinically distinct subset of HNCs. Unlike cervical cancer, where HPV infection is typically associated with aggressive invasive disease and poor prognosis, HPV-positive HNCs generally present a more favourable clinical outcome, particularly among non-tobacco users. Conversely, HPV-negative HNC patients who are predominantly tobacco and/or alcohol users, exhibit a poor prognosis and lower survival rate. Despite significant advances in treatment strategies for HNCs, therapy resistance leading to aggressive tumor recurrence and mortality remains to be a major clinical challenge. Transcription factors (TFs), as key regulators of gene expression and cellular signalling networks, play a critical role in head and neck carcinogenesis and represent promising targets for cancer therapy. A comprehensive understanding of the transcriptional and post-transcriptional/translational regulation of TFs, as well as the molecular mechanism(s) underlying their dual role as oncogenes or tumor suppressors, is essential for the development of effective therapies. This review focuses on major transcriptional regulators transcriptional regulators with establishd or emerging relevance in HNC pathobiology including AP-1, NF-κB, STAT3 MYC, SOX2, YY1, p53, p63 and NOTCH1. We discuss their oncogenic, tumor suppressive and context-dependent functions, with emphasis on how these factors coordinate downstream signalling networks during HNC development and progression, and therapeutic resistance. Overall, dysregulation of transcription factor in HNC is not limited to single pathway activation. Instead, TFs interact with non-coding RNAs and epigenetic mechanisms to form interconnected regulatory networks that promote both tumor plasticity and create potential therapeutic opportunities. Effective targeting of these networks will require biomarker-guided and rational combination strategies tailored to tumor type.
The vitamin rheostat: A unified model of epigenetic feedback in vitamin homeostasis.
Kubant R, Anderson GH, Korda M
Biochim Biophys Acta Gene Regul Mech · 2026 Jun · PMID 42372945 · Publisher ↗
Recent evidence implicates epigenetic mechanisms in vitamin metabolism, yet most studies remain focused on individual vitamins. In this mini-review, we extend beyond single-vitamin paradigms to propose the Vitamin Rheost...
Recent evidence implicates epigenetic mechanisms in vitamin metabolism, yet most studies remain focused on individual vitamins. In this mini-review, we extend beyond single-vitamin paradigms to propose the Vitamin Rheostat: a unifying model in which vitamins influence regulatory signaling networks that shape their own uptake, utilization, and degradation. By integrating fat-soluble vitamins (nuclear receptor-mediated signaling) and water-soluble vitamins (methyl-donor and enzymatic cofactor systems), this model provides a predictive and experimentally testable framework that may help explain inter-individual variability in response to vitamin intake. It repositions epigenetics as an active mediator in vitamin homeostasis and supports the development of chromatin-informed approaches to precision nutrition.
Post-transcriptional regulation in cancer chemoresistance.
De Lella S, Esposito F, Matassa DS … +1 more , Avolio R
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42372837 · Publisher ↗
Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular diseases. Although cancer-specific mortality rates have declined due to advances in early detection and therapeutic strategies,...
Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular diseases. Although cancer-specific mortality rates have declined due to advances in early detection and therapeutic strategies, the absolute number of cancer-related deaths continues to rise, driven by increasing disease incidence associated with population aging and lifestyle factors. A substantial proportion of cancer mortality is attributable to the development of resistance to anticancer therapies, making drug resistance a critical barrier to durable treatment efficacy and a major focus for clinical and translational research. Drug resistance arises from a wide spectrum of molecular and microenvironmental adaptations that enable cancer cells to limit drug uptake, neutralize or bypass drug activity, and evade therapy-induced cell death. These adaptive processes are orchestrated by extensive rewiring of gene expression programs, regulatory networks, and signaling pathways, ultimately reshaping cellular metabolism and stress responses. Traditionally, such adaptations have been primarily ascribed to genetic alterations and transcriptional reprogramming. However, growing evidence indicates that posttranscriptional regulatory mechanisms play a pivotal and previously underappreciated role in modulating gene expression and protein activity during the acquisition of drug-resistant phenotypes. RNA-mediated mechanisms, including regulation of mRNA stability, translation, subcellular localization, and RNA-protein interactions, introduce a dynamic and reversible level of control over protein expression and activity. In particular, non-canonical RNA-binding proteins, diverse classes of non-coding RNAs, and riboregulatory mechanisms have emerged as critical modulators of pathways involved in drug transport, DNA damage response, apoptosis, and metabolic adaptation. These processes allow cancer cells to rapidly fine-tune functional proteomes without requiring permanent genetic changes, thereby facilitating phenotypic plasticity and therapeutic escape. In this review, we summarize recent advances in the field, with a particular emphasis on emerging posttranscriptional mechanisms of gene regulation that contribute to anticancer drug resistance. By highlighting the dynamic and multilayered nature of RNA-mediated regulatory processes, we aim to provide a comprehensive framework for understanding how cancer cells adapt to therapeutic pressure and to identify novel avenues for therapeutic intervention in the context of drug-resistant disease.
Effect of Ca and Mg on the conformational dynamics of membrane-anchored Bcl-xL.
Nguyen Q, Freites JA, Ladokhin AS … +1 more , Tobias DJ
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42372816 · Publisher ↗
Mg and Ca are involved in nearly every aspect of cellular function. These divalent cations can bind to the same protein binding sites, often with significantly binding affinities, resulting in distinct conformational cha...
Mg and Ca are involved in nearly every aspect of cellular function. These divalent cations can bind to the same protein binding sites, often with significantly binding affinities, resulting in distinct conformational changes in proteins. Recent studies demonstrated that both Mg and Ca can influence lipid-dependent folding and insertion of various membrane-active peptides and non-constitutive membrane proteins and peptides. Specifically, cardiolipin, can recruit various apoptotic regulators of the Bcl-2 family (e.g., pro-apoptotic BAX and anti-apoptotic Bcl-xL) to the model membranes in the absence of canonical protein activators, like the BH3-only proteins. This interaction can only occur in the presence of divalent cations, such as Mg which is constantly present outside of the targeted mitochondrial membrane in the cell, or Ca, which is released from the mitochondria at the early stages of apoptosis. Here, we use all-atom molecular dynamics simulations to provide the first atomistic-level characterization of the dynamic protein-lipid-cation interaction of the Bcl-xL, anchored to the cardiolipin-containing lipid bilayer, in the presence of either Mg or Ca. Our results show that both ions interact with Bcl-xL and membrane lipids in the membrane-anchored state, but through distinct modes. Whereas Mg primarily forms water-mediated interactions with both the protein and the lipids, Ca establishes direct contacts with both. These differences led to more constrained conformational dynamics of Bcl-xL in the presence of Ca, particularly in the α1-α2 loop and the BH3-binding groove involved in inhibitory interactions with pro-apoptotic BAX.
Compositional analysis and functional insights of the cell envelope in Synechocystis sp. PCC 6803.
Piano D, Haniewicz P, Farci D
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42372815 · Publisher ↗
The cell envelope of Synechocystis sp. PCC 6803 has a Gram-negative-like organization, with inner and outer membranes and an outermost surface layer. A comprehensive characterization of its layered structure, considering...
The cell envelope of Synechocystis sp. PCC 6803 has a Gram-negative-like organization, with inner and outer membranes and an outermost surface layer. A comprehensive characterization of its layered structure, considering the presence of pigments and distinctive proteins, has not yet been established. Here, we isolated cell envelope fragments and characterized them by electrophoretic and proteomic analyses identifying a recurring set of inner membrane, outer membrane, and S-layer proteins, including six conserved porins and additional associated proteins with repeated beta-strand motifs, among which several contain a SLH domain. Further characterization by absorption spectroscopy, to investigate the typical orange color of this cell envelope, revealed extended retention of carotenoids. These results provide an integrated and preliminary view of the Synechocystis sp. PCC 6803 cell envelope and its characteristic proteome.
Ferroptosis in the tumor immune microenvironment: A double-edged sword in immunotherapy.
Yang R, Zhu T, Jiang J … +2 more , Deng M, Miao J
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42365903 · Publisher ↗
Ferroptosis, an iron-dependent form of programmed cell death, has recently garnered significant attention for its intricate involvement in the tumor immune microenvironment (TIME) and its implications in tumor immunother...
Ferroptosis, an iron-dependent form of programmed cell death, has recently garnered significant attention for its intricate involvement in the tumor immune microenvironment (TIME) and its implications in tumor immunotherapy. This review comprehensively explores the molecular mechanisms underlying ferroptosis and its regulation within tumor cells, highlighting the complex dual effects of ferroptosis on immune cell functions in TIME. While ferroptosis enhances cancer cell immunogenicity and promotes antitumor immunity through immune cell activation, it may also impair immune responses by disrupting T/B/NK cell functions and macrophage polarization. Critically, ferroptotic cells release damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and oxidized phospholipids, triggering inflammation via receptors like Toll-like receptor 4 (TLR4) and activating inflammasomes. This review explores how this ferroptosis-driven inflammatory cascade reshapes TIME components, highlighting its potential to sensitize tumors to immunotherapy. Targeting ferroptosis pathways may overcome resistance to immune checkpoint blockade. However, cancer cells develop ferroptosis resistance through metabolic adaptations and antioxidant systems, complicating therapeutic strategies. Future studies should unravel context-specific regulatory networks linking ferroptosis, inflammation, and immunity to optimize immunotherapy efficacy.
Neural-tumor crosstalk in driving tumor metabolic reprogramming.
Xiao X, Zhang C, Chen J … +4 more , Zhang J, Li H, Yu W, Cai X
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42365902 · Publisher ↗
Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that clas...
Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.
Cellular prion protein suppresses colitis and colorectal carcinogenesis via modulating inflammatory responses.
Zhao T, Wang W, Wang Q … +10 more , Fan W, Zhang X, Jin L, Gong C, Zhang X, Jiang B, Ma J, Yuan C, Ma J, Zhao Y
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42364787 · Publisher ↗
Reducing prion protein (PrP) levels is a leading therapeutic strategy against prion disease. However, the normal function of PrP remains incompletely understood, creating uncertainty about the potential consequences of t...
Reducing prion protein (PrP) levels is a leading therapeutic strategy against prion disease. However, the normal function of PrP remains incompletely understood, creating uncertainty about the potential consequences of this approach. We investigated the role of PrP on intestinal tumorigenesis using the Apc familial adenomatous polyposis model and the Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) induced colitis-associated colorectal cancer model. In Prnp background, both tumor burden and survival rates of Apc mice were significantly improved; in contrast, the absence of PrP significantly intensified AOM/DSS-induced carcinogenesis. PrP's capability to promote cell proliferation accounts for the findings in Apc mice, but it cannot explain the substantial increase in carcinogenesis in AOM/DSS model. We found that AOM/DSS-treated Prnp mice had elevated numbers of pro-inflammatory M1 macrophages, which transitioned to an antigen-presenting state, thereby prolonging the inflammatory response. In bone marrow-derived macrophages (BMDMs), the absence of PrP resulted in delayed but sustained NFκB nuclear localization, leading to an extended inflammatory response to lipopolysaccharide (LPS). The exacerbated chronic inflammatory response in Prnp mice was further corroborated by LPS-induced colitis, which resulted in more severe diarrhea, higher levels of pro-inflammatory cytokine expression, and increased infiltration of CD4+ cell during the later phases of inflammation. Our results indicate that PrP deletion delays and extends the inflammatory response, resulting in severer colitis and associated colorectal carcinogenesis. These findings raise the potential implication that monitoring for chronic inflammation may be warranted in patients undergoing PrP-reduction therapy.
CircUBAP2 promotes intrahepatic cholangiocarcinoma progression via PRMT1-p65 methylation and the miR-642b-5p/IL-1β axis.
Li C, Liu S, Chen C … +7 more , Cao K, Chen R, Xu X, Chang J, Zhang Y, Li C, Li X
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42364786 · Publisher ↗
Intrahepatic cholangiocarcinoma (ICC) frequently exhibits inflammatory signaling and poor outcomes, yet upstream regulators that maintain NF-κB activity remain incompletely defined. Here, we identified circUBAP2 (hsa_cir...
Intrahepatic cholangiocarcinoma (ICC) frequently exhibits inflammatory signaling and poor outcomes, yet upstream regulators that maintain NF-κB activity remain incompletely defined. Here, we identified circUBAP2 (hsa_circ_0001851) by circRNA microarray and validated it in 76 paired ICC tissues and cell lines. Higher circUBAP2 levels were associated with advanced stage and poorer survival. Gain- and loss-of-function assays showed that circUBAP2 enhanced proliferation and migration in vitro and promoted tumor growth and liver metastasis in vivo, accompanied by increased NF-κB activity. Biotinylated RNA pull-down coupled with mass spectrometry and RIP confirmed an interaction between circUBAP2 and PRMT1, which was accompanied by reduced PRMT1-p65 association and decreased inhibitory p65 R30 dimethylation. PRMT1 ChIP-seq further revealed altered chromatin occupancy and motif enrichment in circUBAP2-overexpressing cells, with NF-κB motifs no longer among the top enriched motifs. In parallel, circUBAP2 sponged miR-642b-5p, thereby relieving miR-642b-5p-mediated repression of IL1B and increasing IL-1β expression. Pharmacologic IL-1 receptor blockade with anakinra attenuated circUBAP2-associated tumor growth in vivo. Collectively, these data identify circUBAP2 as a candidate prognostic biomarker and suggest that IL-1-targeted strategies warrant evaluation in circUBAP2-high ICC.
ACSS2 promotes macrophage senescence and atherosclerosis by upregulating histone H3 lysine 9 crotonylation.
Yin Q, Yang J, Xu Y … +14 more , Qi Z, Wang X, Zhu X, Jing Y, Chen J, Min J, Lu H, Wei H, Li X, Chao M, Li X, Chen X, Chen H, Jiang H
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42364785 · Publisher ↗
Atherosclerosis (AS) is an aging-related chronic inflammatory disease. Histone lysine crotonylation (Kcr) is a posttranslational modification, which is widespread as acetylation; however, its roles are largely unknown in...
Atherosclerosis (AS) is an aging-related chronic inflammatory disease. Histone lysine crotonylation (Kcr) is a posttranslational modification, which is widespread as acetylation; however, its roles are largely unknown in senescent macrophage of atherosclerosis. In this study, we report that histone Kcr of macrophages is abnormally elevated in atherosclerosis. Here, we show that ACSS2 (acyl-CoA synthetase short chain family member 2) is identified to increase the histone 3 lysine 9 crotonylation (H3K9cr) level in macrophages. Mechanistically, under pathological stimuli, the elevated ACSS2 increases H3K9cr expression, which enriches at the promoter of senescence-associated secretory phenotype genes, driving senescence and atherosclerosis. Functional analysis demonstrates that ACSS2 knockdown inhibits atherosclerosis in male mice by decreasing H3K9cr expression. We also verify the ACSS2 specific inhibitor, VY-3-135, as a potentially promising therapeutic agent for alleviating atherosclerosis. Furthermore, increased ACSS2 and H3K9cr correlate with senescence in human atherosclerotic lesions. Collectively, our work lays foundation for understanding the macrophage senescence mediated by Kcr and provides a potential therapeutic target for AS.
The tumor-nerve-immune electrical axis: A hypothesis-generating framework for electrochemical communication in cancer.
Zhao PY, Jin WL
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42364784 · Publisher ↗
The tumor microenvironment (TME) is traditionally studied through biochemical, metabolic, and mechanical lenses. Increasing evidence, however, indicates that ion channels, membrane potential, and local ionic conditions a...
The tumor microenvironment (TME) is traditionally studied through biochemical, metabolic, and mechanical lenses. Increasing evidence, however, indicates that ion channels, membrane potential, and local ionic conditions also influence tumor and immune cell behavior, while cancer neuroscience has revealed that neural inputs can regulate tumor growth and plasticity. Despite these parallel advances, an integrated framework that explicitly links tumor bioelectricity, neural signaling, and immune electrochemical responsiveness is lacking. Here, we propose the tumor-nerve-immune electrical axis as a hypothesis-generating framework to organize these adjacent fields. We distinguish three levels of evidence: (i) compartment-specific mechanisms (tumor-cell bioelectricity, tumor-associated neural regulation, immune-cell electrophysiology), (ii) supported pairwise interactions (e.g., neuron-tumor coupling in selected cancers, extracellular K-mediated T-cell suppression), and (iii) testable hypotheses that require direct experimental validation. The framework centers on three components, the electrical phenotype of cancer cells, activity-dependent signaling of tumor-associated nerves, and the capacity of immune cells to interpret ionic and membrane-state cues, and introduces the organizing concepts of neurogenic niche, electro-immunosuppression, and signal interception, all explicitly presented as testable heuristics rather than established universal mechanisms. Current evidence is strongest for individual components and selected pairwise interactions; direct demonstration of a broadly applicable tripartite electrical axis remains limited. We discuss experimentally testable predictions and therapeutic implications, including ion-channel-targeted pharmacology, physical field-based interventions, and emerging bioelectronic platforms. This framework is intended to guide mechanistic studies and evidence-based evaluation of when and how electrical communication contributes to cancer progression.
Regular exercise improves cardiac dysfunction in Drosophila by inhibiting excessive mitochondrial fission through RalA.
Huang W, Ding M, Yi Q … +6 more , Li Y, Gu W, Zhang P, Tian R, Zhang Z, Zheng L
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42362123 · Publisher ↗
Metabolic disorders leading to cardiac dysfunction have become a global health challenge, and the cardioprotective mechanisms of regular exercise remain unclear. This study focused on the small GTPase RalA and revealed i...
Metabolic disorders leading to cardiac dysfunction have become a global health challenge, and the cardioprotective mechanisms of regular exercise remain unclear. This study focused on the small GTPase RalA and revealed its critical role in exercise-mediated improvement of high-fat-induced cardiac dysfunction. Using a high-fat-fed drosophila heart model, combined with genetic manipulation and exercise intervention, it was demonstrated that a high-fat diet upregulates RalA expression in the myocardium, accompanied by excessive mitochondrial fission and impaired cardiac function. Regular exercise not only effectively reversed these pathological phenotypes but also exerted its protective effects in a RalA -dependent manner within the myocardium. Mechanistically, RalA appeared to exert its effects not through traditional energy metabolism pathways, but rather through the regulation of Drp1-mediated mitochondrial fission, thereby preserving mitochondrial network homeostasis and energy supply in cardiomyocytes. This study is the first to propose a novel "exercise-RalA-mitochondrial dynamics" signaling axis, providing new mechanistic insight into the cardioprotective effects of exercise and suggesting that targeting the RalA pathway may represent a promising therapeutic strategy for metabolic heart disease.
Nerve growth factor receptor (NGFR): A key player in glioblastoma progression.
Kidder BM, Vengoji R, Batra SK … +1 more , Shonka N
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42362096 · Publisher ↗
Glioblastoma (GBM) is a highly invasive brain cancer arising from astrocytes, and current treatments are often ineffective, limiting patient five-year survival to <5%, despite maximal safe resection, temozolomide (TMZ) c...
Glioblastoma (GBM) is a highly invasive brain cancer arising from astrocytes, and current treatments are often ineffective, limiting patient five-year survival to <5%, despite maximal safe resection, temozolomide (TMZ) chemotherapy, and radiotherapy. Alterations in receptor tyrosine kinase (RTK) signaling are a hallmark of GBM progression and invasion. Numerous clinical trials have explored commonly altered RTKs, but none have offered a viable target that effectively increases patient outcomes and survival. This review synthesizes available literature on the role of the nerve growth factor receptor (NGFR), particularly the p75 neurotrophin receptor (p75NTR), in GBM progression. p75NTR is a member of the tumor necrosis factor receptor (TNFR) superfamily and is a "death receptor" that lacks intrinsic kinase activity, distinguishing it fundamentally from RTKs such as TrkA, which also serves as a receptor for the nerve growth factor ligand. p75NTR expression is markedly enhanced relative to normal brain tissue, and its signaling is differentially regulated, where p75NTR has roles in supporting tumor invasion, hypoxic adaptation, stemness maintenance, and resistance to conventional TMZ and radiation therapy. p75NTR drives GBM invasion through neurotrophin-dependent mechanisms and through proteolytic cleavage by α- and γ-secretases. Under hypoxic conditions, p75NTR stabilizes HIF-1α and HIF-2α, further promoting angiogenesis, immune evasion, and stem cell phenotypes. By synthesizing available NGFR and GBM data, this review identifies p75NTR as the primary NGFR implicated in GBM progression and positions it as a rationally supported therapeutic target for GBM. This review also identifies key questions warranting further investigation into p75NTR's molecular mechanisms.
From membrane disruption to intracellular targets: A solid-state NMR perspective on antimicrobial peptide mechanism.
Zhang Y, Zou Y, Yang J
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42362036 · Publisher ↗
Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics due to their broad-spectrum activity and low tendency to induce resistance. Based on their modes of action, AMPs are generally classifi...
Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics due to their broad-spectrum activity and low tendency to induce resistance. Based on their modes of action, AMPs are generally classified as membrane-active or intracellular-targeting peptides. Rational design of next-generation AMPs with enhanced efficacy and reduced cytotoxicity requires a detailed understanding of their antimicrobial mechanisms. Solid-state nuclear magnetic resonance (ssNMR) has emerged as a powerful tool for probing AMP-target interactions, providing high-resolution structural and dynamic information under native-like membrane conditions. This review summarizes recent advances in ssNMR methodologies applicable in model membranes and intact cells and highlights their contributions to elucidating AMP antimicrobial mechanisms. Representative investigations reveal that the membrane-active peptide protegrin-1 disrupts lipid bilayers via a toroidal pore mechanism, whereas lipid II-targeting AMPs inhibit cell wall biosynthesis by immobilizing lipid II through supramolecular assembly.
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