Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
Orosomucoid 2 as an immunometabolic regulator in cardiometabolic disease: Molecular mechanisms and translational potential.
Sun X, Shen W, Tang X … +2 more , Shen C, Yuan G
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42402268 · Publisher ↗
Cardiometabolic diseases are driven by persistent crosstalk between metabolic dysfunction and chronic low-grade inflammation. Orosomucoid 2 (ORM2), a highly glycosylated acute-phase protein of the α1-acid glycoprotein fa...
Cardiometabolic diseases are driven by persistent crosstalk between metabolic dysfunction and chronic low-grade inflammation. Orosomucoid 2 (ORM2), a highly glycosylated acute-phase protein of the α1-acid glycoprotein family, has conventionally been considered a circulating inflammatory marker. Recent evidence, however, suggests that ORM2 may also function as an active immunometabolic regulator linking hepatic stress responses, adipose tissue inflammation, macrophage polarization, and systemic metabolic homeostasis. This review summarizes the molecular characteristics, tissue distribution, glycosylation-dependent biology, and stress-responsive regulation of ORM2, with emphasis on cytokine-induced JAK/STAT and NF-κB signaling, hepatic and extrahepatic ORM2 expression, and potential glycoform-specific regulation. Macrophage polarization is discussed as a central mechanism through which ORM2 may modulate inflammatory resolution, adipose-liver communication, insulin sensitivity, vascular inflammation, and myocardial injury. Particular attention is given to the possibility that increased ORM2 may represent a compensatory response to inflammatory-metabolic stress rather than simply a marker of disease burden. The translational potential of ORM2 is also considered, including its possible use in multi-marker biomarker panels for cardiometabolic risk stratification and treatment monitoring. However, major limitations remain, including incomplete mechanistic knowledge, unclear receptor biology, limited data on ORM2 glycosylation in specific cardiometabolic phenotypes, assay standardization issues, and insufficient prospective clinical validation. In summary, ORM2 appears to be a biologically plausible mediator linking inflammation and metabolism, but further mechanistic and clinical studies are required to establish its causal role, biomarker value, and therapeutic potential in cardiometabolic disease.
In vivo dysregulation of insulin and glucagon secretion: Disturbed mitochonderial VDAC1 expression and localization in pancreatic β-cells convey global insulin secretory defects in diabetic GK rat.
Salehi A, Al-Amily IM, Parandeh F … +2 more , Östenson CG, Lundquist I
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42402267 · Publisher ↗
The mildly diabetic Goto-Kakizaki (GK) rat is widely used to study type 2 diabetes (T2D), yet the mechanisms underlying defective insulin secretion in this model remain incompletely understood. We therefore investigated...
The mildly diabetic Goto-Kakizaki (GK) rat is widely used to study type 2 diabetes (T2D), yet the mechanisms underlying defective insulin secretion in this model remain incompletely understood. We therefore investigated the effects of multiple secretagogues on insulin and glucagon secretion as well as on blood glucose in vivo, followed by mechanistic studies assessing insulin secretion, ATP content and mitochondrial VDAC1/VDAC2 expression in isolated islets from young and aged GK rats. The in vivo study revealed severely impaired insulin responses to various secretagogues in GK rats resulting in lack of suppressive effect on glucagon release and elevated blood glucose as compared to Wistar rats. The in vitro experiments showed that isolated islets from GK rats exhibited defective insulin secretion, which further deteriorated with age. This was associated with reduced VDAC2 expression at young age followed by increased VDAC1 expression, along with aberrant mistargeting of VDAC1 to the β-cell plasma membrane, leading to ATP loss and further diminished glucose-stimulated insulin secretion at old age. Pharmacological inhibition or antibody targeting of VDAC1 restored insulin secretion. Complementary studies in INS-1832/13 cells showed the chronic hyperglycemia increases VDAC1 expression and reduces cell viability, effects counteracted by activation of the cAMP/PKA pathway. These findings identify dysregulated VDAC1/VDAC2 expression and VDAC1 mistargeting to cell surface as key contributors to β-cell dysfunction in GK rats, particularly with aging, and suggest VDAC1 as a potential therapeutic target in early-stage of T2D.
B3GNT2 promotes gastric cancer metastasis by facilitating membrane trafficking of RYK via N-glycosylation.
Fu Y, Wang Y, Cai Z … +3 more , Huang S, Chen J, Ye J
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42402266 · Publisher ↗
BACKGROUND: Gastric cancer (GC) is characterized by a high metastatic propensity, which constitutes the primary cause of poor patient prognosis. Receptor-like tyrosine kinase (RYK) is associated with GC metastasis, but i...
BACKGROUND: Gastric cancer (GC) is characterized by a high metastatic propensity, which constitutes the primary cause of poor patient prognosis. Receptor-like tyrosine kinase (RYK) is associated with GC metastasis, but its regulatory mechanism remains unclear. METHODS: Primary and metastatic GC tissues, together with their matched adjacent non-tumor samples, were collected. GC cell models were established to systematically evaluate the driver role of RYK in GC metastasis. We further integrated clinical specimens, GC cell models, and a mouse model of GC liver metastasis, and combined immunohistochemistry, real-time quantitative PCR, Western blot, flow cytometry, immunofluorescence, wound-healing assays, 3D sphere invasion assays, and co-immunoprecipitation to elucidate the biological functions and molecular mechanisms of RYK in GC metastasis. RESULTS: RYK expression was higher in both primary and metastatic tumor tissues than in adjacent normal tissues. Overexpression of RYK markedly enhanced the invasion and migration capacities of GC cells and induced epithelial-to-mesenchymal transition; blocking its membrane localization promptly attenuated this pro-metastatic effect. Mechanistically, β-1,3-N-acetylglucosaminyltransferase 2 (B3GNT2) bound to RYK and catalyzed its N-glycosylation, thereby promoting RYK trafficking to the plasma membrane. In GC cell models and a liver-metastasis mouse model, GC cells overexpressing B3GNT2 displayed significantly increased metastatic ability, whereas treatment with an N-glycosylation inhibitor effectively suppressed this phenomenon. CONCLUSION: B3GNT2 promotes the trafficking of RYK to the plasma membrane of GC cells by mediating its N-glycosylation, thereby driving GC metastasis.
Retraction notice to "S-allyl cysteine in combination with clotrimazole downregulates Fas induced apoptotic events in erythrocytes of mice exposed to lead" [Biochimica et Biophysica Acta (BBA) - General Subjects 1820 (2012) 9-23].
Mandal S, Mukherjee S, Chowdhury KD … +8 more , Sarkar A, Basu K, Paul S, Karmakar D, Chatterjee M, Biswas T, Sadhukhan GC, Sen G
Biochim Biophys Acta Gen Subj · 2026 Jul · PMID 42401523 · Publisher ↗
Abstract loading — click title to view on PubMed.
Retraction notice to "Regulatory role of nitric oxide in the reduced survival of erythrocytes in visceral leishmaniasis" [Biochimica et Biophysica Acta (BBA) - General Subjects 1800 (2010) 964-976].
Chowdhury KD, Sen G, Biswas T
Biochim Biophys Acta Gen Subj · 2026 Jul · PMID 42401522 · Publisher ↗
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Focadhesin interacts with SALL4 to regulate EGFR signaling and oncogenesis in non-small cell lung cancer.
Lu X, Gu Y, Ye W … +2 more , Wang H, Ou WB
Biochim Biophys Acta Mol Cell Res · 2026 Jul · PMID 42398861 · Publisher ↗
Owing to drug resistance to therapeutic targets, there is an urgent demand to find and validate new potent targets for non-small cell lung cancer (NSCLC). Although high SALL4 expression significantly promotes lung cancer...
Owing to drug resistance to therapeutic targets, there is an urgent demand to find and validate new potent targets for non-small cell lung cancer (NSCLC). Although high SALL4 expression significantly promotes lung cancer growth, its oncogenic mechanism remains unclear. In the current study, focal adhesion molecular focadhesin (FOCAD), a candidate that has interacted with oncofetal SALL4, was identified by SALL4 immunoprecipitation and mass spectrometry. Immunoprecipitation, immunofluorescence stains, cell component separation, and molecular docking demonstrated the interaction of SALL4 and FOCAD. Immunoblotting and/or TCGA dataset analysis showed high expression of SALL4 and FOCAD paralleled in lung adenocarcinoma but not in lung squamous cell carcinoma. FOCAD knockdown resulted in dramatic inhibition of cell viability, colony formation, xenograft growth, wound healing, and invasion; apoptotic induction; and G-phase blockade in NSCLC cell lines through suppression of the EGFR or IGF1R signaling pathways and expression of FAK and β-catenin. Conversely, SALL4 overexpression partially attenuated the inhibition of cell viability and colony formation of FOCAD silencing in these cells. The combination of FOCAD shRNA knockdown with osimertinib treatment showed additive anti-tumor activity in NSCLC cell lines. Furthermore, FOCAD silencing also showed markedly anti-proliferative effects in the osimertinib-resistant NSCLC cell line. These findings demonstrate that FOCAD in NSCLC is generally associated with SALL4 and EGFR expressions and activation. There are functional correlations between FOCAD and SALL4, and targeting FOCAD could be an effective therapeutic strategy in both osimertinib-sensitive and -resistant NSCLC.
An AAV-based bioluminescent reporter reveals dynamic YAP/TAZ-TEAD transcriptional activity during liver injury.
Ye J, Luo C, Yang Z … +9 more , Fan Y, Gu L, Xu G, You X, Feng Y, Wang H, Jia R, Yuan Z, Chen J
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42398167 · Publisher ↗
YAP/TAZ are central mechanosensitive regulators of liver injury, fibrosis, and regeneration; however, their dynamic activity in vivo remains challenging to monitor. Here, we establish an AAV8-delivered bioluminescent rep...
YAP/TAZ are central mechanosensitive regulators of liver injury, fibrosis, and regeneration; however, their dynamic activity in vivo remains challenging to monitor. Here, we establish an AAV8-delivered bioluminescent reporter system (rAAV-8 × GTIIC-Luc) that enables real-time, non-invasive, and longitudinal visualization of hepatic YAP/TAZ-TEAD transcriptional activity. Small-molecule inhibitors targeting the upstream kinases LATS1/2 were employed to pharmacologically perturb YAP/TAZ activity, resulting in robust induction of reporter activity both in cultured cells and in mouse liver. Using a carbon tetrachloride (CCl₄)-induced mouse model of liver injury and fibrosis, we observed a characteristic biphasic pattern of hepatocellular YAP/TAZ-TEAD transcriptional activity, with an early increase followed by a gradual decline during continued injury and a further reduction upon CCl₄ withdrawal. Genetic ablation of YAP in hepatocytes markedly attenuated reporter signals throughout this process, supporting a dominant contribution of YAP to TEAD-dependent transcriptional programs in this context. Together, these results establish rAAV-8 × GTIIC-Luc as a robust platform for in vivo monitoring of YAP/TAZ-TEAD transcriptional dynamics and provide temporal insights into pathway regulation during liver injury, with broad applicability for mechanistic studies and drug evaluation.
Macropinocytosis: A central orchestrator in tumor development and therapeutic resistance.
Wang C, Wang X, Jiang Z … +5 more , Zhao J, Wang X, Liu Y, Yuan J, Jiao Y
Biochim Biophys Acta Rev Cancer · 2026 Jul · PMID 42392514 · Publisher ↗
Macropinocytosis, a dysregulated endocytic pathway prevalent in cancers, drives tumor progression by scavenging extracellular nutrients and activating oncogenic signaling. This review proposed a functional categorization...
Macropinocytosis, a dysregulated endocytic pathway prevalent in cancers, drives tumor progression by scavenging extracellular nutrients and activating oncogenic signaling. This review proposed a functional categorization of macropinocytosis based on the basal activity and stimulus origin. We then delineated the specific signaling networks governing this process and its cell type-specific functions within the tumor microenvironment, which collectively fuel malignant phenotypes and modulate diverse cell death modalities, including ferroptosis, cuproptosis, and alkaliptosis. Furthermore, we critically evaluated the therapeutic potential of targeting macropinocytosis in oncology, highlighting synergistic combination strategies and outlining key future directions such as the identification of specific biomarkers, exploration of non-canonical functions, and elucidation of its role in intercellular communication. This synthesis reframes macropinocytosis from a mere metabolic adaptation to a central orchestrator of tumor biology, thereby providing a robust rationale for its therapeutic inhibition in cancer.
Small-molecule LIFR inhibitors attenuate renal tubulointerstitial fibrosis.
Zhou JX, Long TT, Liu Y … +9 more , Ma JY, Ma YY, Chen QZ, Sun PX, Zhang R, Hu Z, Zhou MM, Zhu FX, Nie J
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42392460 · Publisher ↗
Renal tubulointerstitial fibrosis (TIF), the final common pathway of chronic kidney disease (CKD), is driven by pathological crosstalk between fibroblasts and tubular epithelial cells (TECs). Leukemia inhibitory factor (...
Renal tubulointerstitial fibrosis (TIF), the final common pathway of chronic kidney disease (CKD), is driven by pathological crosstalk between fibroblasts and tubular epithelial cells (TECs). Leukemia inhibitory factor (LIF) contributes to this cellular interaction by binding to LIF receptor (LIFR) and activating downstream ERK and STAT3 pathways. While novel LIFR small-molecule inhibitors EC330 and EC359 have shown therapeutic efficacy in cancer, their potential in treating kidney diseases remains unexplored. Here, we showed that LIF and LIFR were expressed at low levels in healthy adult kidneys but markedly upregulated in fibrotic kidneys, particularly in fibroblasts and TECs. Mechanistically, transforming growth factor-β1 (TGF-β1) drove LIF and LIFR expression in both cell types via a SMAD3-dependent pathway. Both EC330 and EC359 dose-dependently suppressed fibroblast activation and TEC pro-fibrotic responses induced by LIF or TGF-β1, with EC330 exhibiting a superior safety profile. In vivo, EC330 attenuated ERK and STAT3 phosphorylation in fibroblasts and TECs, significantly mitigating both developing TIF in the unilateral ischemia-reperfusion injury model and established TIF in the aristolochic acid model. Collectively, our findings demonstrate that LIFR inhibition is a viable anti-fibrotic strategy and identify EC330 as a promising drug candidate for treating CKD.
METTL3 mediates Ang-II-induced cardiac hypertrophy by regulating KLF5 expression in an mA-dependent manner.
Cai C, Jiang Y, Wang Y … +1 more , Chen Z
Biochim Biophys Acta Gene Regul Mech · 2026 Jul · PMID 42392401 · Publisher ↗
BACKGROUND: Cardiac hypertrophy is a pivotal pathological process leading to heart failure, driven by chronic stress, pressure overload, and neurohormonal stimulation, such as Angiotensin II (Ang II). Although METTL3-med...
BACKGROUND: Cardiac hypertrophy is a pivotal pathological process leading to heart failure, driven by chronic stress, pressure overload, and neurohormonal stimulation, such as Angiotensin II (Ang II). Although METTL3-mediated mA modification has been implicated in cardiovascular diseases, the precise role and underlying mechanism of the KLF5 in Ang II-induced myocardial hypertrophy remain poorly understood. METHODS: H9C2 and AC16 cardiomyocytes were treated with Ang II to establish an in vitro hypertrophy model. The expression of METTL3, KLF5, and hypertrophic markers (ANP, BNP, and β-MHC) was quantified using RT-qPCR and Western blot. Functional validation was performed via lentiviral-mediated knockdown and overexpression. The direct interaction and mA modification of KLF5 mRNA were validated using RIP-qPCR and MeRIP-qPCR assays. Cardiomyocyte surface area and α-actinin distribution were assessed by immunofluorescence. mRNA stability was determined by Actinomycin D assays. RESULTS: Ang II stimulation significantly upregulated the expression of METTL3 and KLF5 in a dose-dependent manner. Silencing of either METTL3 or KLF5 effectively attenuated Ang II-induced cardiomyocyte enlargement and suppressed the fetal gene program. Mechanistically, METTL3 was found to promote KLF5 expression by increasing its mA modification levels and enhancing its mRNA stability. Furthermore, rescue experiments demonstrated that the inhibitory effect of METTL3 knockdown on cardiomyocyte hypertrophy was substantially reversed by KLF5 overexpression, confirming that KLF5 is a functional downstream effector of METTL3. CONCLUSIONS: METTL3 facilitates Ang II-induced cardiac hypertrophy by modulating KLF5 expression through an mA-dependent mechanism. Targeting the METTL3/KLF5 axis may offer a novel therapeutic strategy for the treatment of pathological myocardial hypertrophy.
Moderate-altitude hypoxia is associated with attenuated diet-induced liver injury and coordinated carbon-metabolic and lipid remodeling.
Ma Y, Hao E, Zhang T … +6 more , Zhang Y, Huang D, Hou J, Liu Z, Zhao N, Tian M
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jul · PMID 42392304 · Publisher ↗
Chronic mild hypoxia at moderate altitude (2260 m) has been linked to improved systemic metabolism, but its liver-specific associations under high-energy diets remain incompletely defined. In this study, age-matched male...
Chronic mild hypoxia at moderate altitude (2260 m) has been linked to improved systemic metabolism, but its liver-specific associations under high-energy diets remain incompletely defined. In this study, age-matched male C57BL/6 J mice were maintained for 15 weeks at simulated low altitude (50 m) or moderate altitude (2260 m) while fed a normal diet (ND), high-fat diet (HFD), or HFD with 30% fructose (HFD + HFr). Hepatic outcomes were assessed using ultrasonography, histology, electron microscopy, serum biochemistry, targeted energy metabolomics, lipidomics, and immunoblotting. Compared with the corresponding low-altitude high-energy diet groups, mice at 2260 m showed lower diet-associated weight gain, hepatic steatosis, and ALT/AST elevations. Structural analyses showed reduced lipid-droplet accumulation and qualitatively improved mitochondrial ultrastructural appearance. Metabolomics showed coordinated decreases in steady-state intermediates across glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle relative to the 50 m HFD group, together with enzyme changes consistent with reduced lipogenic capacity and altered fatty-acid uptake/oxidation. Lipidomic profiling further showed lower accumulation of neutral lipids, including triglycerides and diacylglycerols, as well as sphingolipids, while phospholipid class-level composition appeared less disturbed. Overall, moderate-altitude exposure was associated with attenuation of high-energy-diet-related hepatic metabolic dysfunction and with coordinated metabolic remodeling. These findings identify chronic mild hypoxia as an important contextual factor associated with hepatic metabolic responses, while direct causal mechanisms require further validation.
The gut microbial lauroyl tryptamine antagonizes oxysterol-GPR183 signaling to modulate lipid-sensitive metabolic pathways in a sex-dependent manner.
von Voss L, Kjær VMS, Smits MM … +8 more , Arora T, Louka S, Beaman EE, Manandhar A, Holst JJ, Ulven T, Qvortrup K, Rosenkilde MM
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jul · PMID 42392303 · Publisher ↗
OBJECTIVES: GPR183, a G protein-coupled receptor activated by oxysterols, regulates immune and metabolic signaling in a sex-dependent manner. Lauroyl tryptamine (LT), a lipid-modified microbial metabolite, was recently i...
OBJECTIVES: GPR183, a G protein-coupled receptor activated by oxysterols, regulates immune and metabolic signaling in a sex-dependent manner. Lauroyl tryptamine (LT), a lipid-modified microbial metabolite, was recently identified as a GPR183 antagonist. We hypothesized that LT disrupts oxysterol-driven metabolic regulation by antagonizing GPR183 activity. METHODS: LT's antagonistic properties were assessed using BRET-based assays for GPR183-mediated arrestin recruitment and G protein signaling. LT absorption was quantified in isolated perfused rat colon. Metabolic outcomes were evaluated in wild-type (WT) and Gpr183 knockout (Gpr183/) mice treated with LT or the synthetic antagonist NIBR189. To examine microbiota contributions, cecal contents from WT and Gpr183/ mice were transplanted into germ-free recipients, and metabolic phenotypes were analyzed. RESULTS: LT selectively inhibited oxysterol (7α,25-OHC)-induced arrestin recruitment via human and mouse GPR183 without altering Gαi signaling. LT was absorbed across the colonic epithelium in a dose-dependent manner. Female mice treated with NIBR189 but not LT exhibited differences in body weight change and glucose homeostasis. Microbiota transfer did not reproduce the phenotype. LT induced weight loss in male WT mice, but not in Gpr183/ males. CONCLUSION: LT functions as a pathway-specific antagonist of oxysterol signaling via GPR183, modulating lipid-sensitive metabolic pathways in a sex-dependent manner.
Size-dependent fluorescence kinetics reveal contributions of intrinsic quenching and singlet-triplet annihilation during LHCII aggregation.
Conradie F, van Heerden B, Gwizdala M … +1 more , Krüger TPJ
Biochim Biophys Acta Bioenerg · 2026 Jul · PMID 42386143 · Publisher ↗
Aggregation of the main antenna complex of higher plants, Light-Harvesting Complex II (LHCII), is widely used as an in-vitro model for energy-dependent quenching (qE), yet fluorescence reduction in aggregates is frequent...
Aggregation of the main antenna complex of higher plants, Light-Harvesting Complex II (LHCII), is widely used as an in-vitro model for energy-dependent quenching (qE), yet fluorescence reduction in aggregates is frequently interpreted without a quantitative separation of intrinsic quenching from excitation-induced annihilation. Here, we address this ambiguity by directly correlating aggregate size, concentration, steady-state fluorescence intensity, and decay kinetics during controlled, incremental aggregation of isolated LHCII. By combining fluorescence correlation spectroscopy (FCS) with time-correlated single-photon counting (TCSPC) in a unified experimental framework, we monitored structural and photophysical changes in real time as detergent removal drives biphasic aggregation. We quantified the aggregate composition from the particle concentrations, enabling direct scaling of the absorption cross-section with aggregate size. The average fluorescence lifetime decreased semi-logarithmically with increases in hydrodynamic radius, whereas steady-state fluorescence intensities deviated strongly from this trend. Intensity-dependent measurements and steady-state kinetic modeling reveal that singlet-triplet annihilation (STA) emerges at moderate excitation intensities and rapidly becomes the dominant contributor to fluorescence quenching, even for relatively small aggregates. In contrast, intrinsic quenching increases more gradually with aggregate size. By quantitatively disentangling intrinsic excitation quenching from annihilation processes, this work demonstrates that STA can govern the apparent photophysical response of aggregated LHCII across excitation regimes commonly considered non-annihilating. The size-dependent mechanistic framework presented here provides a basis for distinguishing intrinsic quenching from annihilation effects in aggregation-based studies of photosynthetic antenna complexes.
Plant uricase are evolutionarily conserved but functionally divergent: A case study of Oryza coarctata uricase.
Rajkumari N, Chowrasia S, Iyyappan Y … +4 more , Roy A, Ahmad N, Singh TP, Mondal TK
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42386052 · Publisher ↗
Allantoin plays a major role in nitrogen mobilization as well as abiotic stress tolerance in plants, and uricase enzyme is the key rate-limiting enzyme for the biosynthesis of allantoin in peroxisomes. However, the molec...
Allantoin plays a major role in nitrogen mobilization as well as abiotic stress tolerance in plants, and uricase enzyme is the key rate-limiting enzyme for the biosynthesis of allantoin in peroxisomes. However, the molecular mechanisms underlying stress-induced allantoin accumulation as well as enhanced uricase activity, along with the evolutionary conservation, structural diversification, and regulatory characteristics of plant uricase enzymes, remain poorly understood. This study investigates evolutionary relationships, functional variations and catalytic mechanisms of the uricase enzymes among 157 plant species. Phylogenetic analysis grouped these species into three major clades, indicating a progression from microalgae to higher plants. Motif analysis revealed the presences of a conserved Pfam01014 (uricase) domain across the species. Uricase activity analysis of 22 representative species showed the highest activity in ureidic legumes, including Vigna radiata and Glycine max, and the lowest in non-leguminous species such as Cucumis sativus. Moreover, promoter analysis of the Uricase gene identified diverse cis-regulatory elements associated with stress, hormone responses and plant development. Structural modelling, docking and sequence alignments revealed conserved substrate-binding residues. Biophysical characterization of recombinantly purified uricase from Oryza coarctata using fluorescence spectroscopy demonstrated uric acid binding with a dissociation constant (K) of 10.89 μM, positive cooperativity, and a Michaelis constant (K) of 23.96 μM. Circular dichroism showed a conformational shift from α-helix to β-sheet upon ligand binding and molecular dynamics simulations supported stable urate interactions in O. coarctata. This work highlights the evolutionary conservation and functional divergence of uricase, featuring unique catalytic adaptations in ureidic legumes.
KIAA0101 in human cancers: From biomarker discovery to therapeutic targeting.
Cao H, Yang S, Sun W … +2 more , Chen X, Zhou J
Biochim Biophys Acta Rev Cancer · 2026 Jul · PMID 42385916 · Publisher ↗
KIAA0101, also known as proliferating cell nuclear antigen (PCNA) clamp-associated factor (PCLAF), is a small PCNA-interacting protein linking DNA replication, DNA damage tolerance, cell-cycle progression, and genome mai...
KIAA0101, also known as proliferating cell nuclear antigen (PCNA) clamp-associated factor (PCLAF), is a small PCNA-interacting protein linking DNA replication, DNA damage tolerance, cell-cycle progression, and genome maintenance. Aberrant KIAA0101 expression occurs across multiple human malignancies and is frequently associated with aggressive clinicopathological features, therapy resistance, and poor survival. Beyond its canonical role as a proliferation-associated PCNA cofactor, emerging evidence obtained from bulk transcriptomics, single-cell sequencing, and spatially resolved analyses suggests that KIAA0101-high tumor states mark proliferative, stem-like, immune-excluded, and treatment-resistant ecosystems. However, research in this field remains limited by descriptive correlations, small retrospective cohorts, isoform-blind assays, and incomplete mechanistic validation. In this review, we synthesize current evidence on the structural features, regulatory networks, cellular functions, disease-specific roles, immune-microenvironmental associations, and translational relevance of KIAA0101 in cancer. We emphasize that its immune-related effects are more plausibly mediated through indirect regulatory routes, including NF-κB- and Wnt/β-catenin-associated programs, rather than through the direct transcriptional control of immune checkpoint genes. We further discuss therapeutic strategies targeting the KIAA0101-PCNA interface, KIAA0101 degradation, RNA interference/CRISPR-based suppression, and rational combinations with DNA damage response inhibitors or approved targeted agents. Future work should prioritize isoform-resolved detection, non-PCNA interactome mapping, immune-competent functional models, and biomarker-driven validation to determine whether KIAA0101 can be advanced from a cancer-associated molecule to a clinically actionable biomarker or therapeutic vulnerability.
Post-translational modifications as hubs of amino acid metabolism in cancer: From oncogenic signaling to therapeutic targeting.
Xu N, Shao J, Jiang L … +2 more , Zhao H, Zheng W
Biochim Biophys Acta Rev Cancer · 2026 Jul · PMID 42385915 · Publisher ↗
Metabolic reprogramming is a hallmark of cancer, characterized by significant alterations in amino acid metabolism to support rapid proliferation and survival. Post-translational modifications (PTMs) have become key regu...
Metabolic reprogramming is a hallmark of cancer, characterized by significant alterations in amino acid metabolism to support rapid proliferation and survival. Post-translational modifications (PTMs) have become key regulatory centers that convert oncogenic signals into metabolic changes. This review systematically examines the interplay between canonical PTMs, including phosphorylation, ubiquitination, acetylation, and methylation, and recently recognized metabolite-sensitive PTMs, including O-GlcNAcylation, lactylation, succinylation, crotonylation, and β-hydroxybutyrylation, in regulating key enzymes and transporters involved in amino acid metabolism. We describe how oncogenic pathways such as PI3K/AKT/mTOR and MYC induce metabolic changes through PTMs, and how amino acid-derived metabolites, in turn, feedback to influence signaling through "metabolite/PTM/signal" loops. Additionally, we emphasize how the PTM-amino acid metabolism axis influences the tumor microenvironment, particularly regarding immune suppression and the remodeling of the extracellular matrix. Finally, we review current clinical and preclinical therapeutic strategies that target PTM-modifying enzymes and PTM-dependent metabolic pathways. Although there are technical and biological challenges, focusing on this axis offers a promising avenue for developing personalized cancer treatments.
Senescence in non-cancerous cells within the tumor: What is the real deal?
Perramon-Güell A, Anerillas C
Biochim Biophys Acta Rev Cancer · 2026 Jul · PMID 42385914 · Publisher ↗
Senescence is a dynamic stress response that not only enforces growth arrest in damaged cells but also profoundly reshapes the tissue microenvironment through secretory programs, immune modulation, and extracellular matr...
Senescence is a dynamic stress response that not only enforces growth arrest in damaged cells but also profoundly reshapes the tissue microenvironment through secretory programs, immune modulation, and extracellular matrix remodeling. In the context of cancer, senescence occurs not only in malignant cells but also in non-cancerous populations, where it can actively influence tumor initiation, progression, and therapy response. This review focuses on senescent non-malignant cells within tumors, exploring how oncogene-induced senescence, therapy-induced senescence, and age-associated niches drive senescence in these compartments and remodel the tumor microenvironment. Finally, we discuss senotherapies (senolytics and senomorphics) and highlight that achieving lineage- and context-selective targeting of senescent non-malignant niches remains a key translational goal that could improve therapy response and reduce relapse.
The MYC network: Hub of malignancy and blueprint for intervention.
Yin H, Liu T, Pan J
Biochim Biophys Acta Rev Cancer · 2026 Jul · PMID 42385913 · Publisher ↗
MYC family transcription factors are central regulators of cell growth, proliferation, metabolism, differentiation, and apoptosis, and their dysregulation contributes to many human cancers. c-Myc, N-Myc, and L-Myc share...
MYC family transcription factors are central regulators of cell growth, proliferation, metabolism, differentiation, and apoptosis, and their dysregulation contributes to many human cancers. c-Myc, N-Myc, and L-Myc share a conserved basic helix-loop-helix leucine zipper domain that mediates MAX dimerization and DNA binding, yet they differ in tissue distribution, developmental roles, modes of activation, and tumor-type associations. In this review, we synthesize current knowledge of the MYC oncogenic network, with emphasis on upstream activation mechanisms, post-translational regulation, transcriptional outputs, structural features relevant to drug discovery, and emerging therapeutic strategies. We discuss how c-Myc and N-Myc integrate oncogenic signaling with chromatin regulation, lineage plasticity, metabolic rewiring, immune modulation, and therapy resistance in a context-dependent manner. We also summarize the therapeutic landscape, including direct disruption of MYC-MAX interactions, stabilization of MAX homodimers, interference with DNA binding, inhibition of transcriptional and epigenetic dependencies, modulation of MYC protein stability, targeted degradation approaches, metabolic interventions, and emerging strategies against extrachromosomal DNA-driven MYC amplification. Recent clinical progress with Omomyc-derived OMO-103 and other MYC-network-targeting agents supports the feasibility of therapeutically intercepting this historically challenging pathway. However, because many MYC-directed strategies affect essential transcriptional, chromatin, and metabolic programs, future development will require careful biomarker selection, rational combinations, and rigorous evaluation of therapeutic windows. By integrating mechanistic and translational literature, this review highlights MYC as a dynamic cancer dependency and discusses opportunities for precision intervention.
GALNT6 localization is associated with gland-forming architecture and morphological differentiation in luminal A breast cancer.
Takahashi K, Uzuki M, Matsuda R … +7 more , Yazawa Y, Kawata K, Shimoyama N, Munakata S, Hashimoto Y, Ohtake T, Kitazume S
Biochim Biophys Acta Gen Subj · 2026 Jul · PMID 42385912 · Publisher ↗
Altered protein glycosylation is a hallmark of cancer and has been implicated in the regulation of tumor cell behavior and tissue organization. N-Acetylgalactosaminyltransferase 6 (GALNT6), an initiating enzyme of mucin-...
Altered protein glycosylation is a hallmark of cancer and has been implicated in the regulation of tumor cell behavior and tissue organization. N-Acetylgalactosaminyltransferase 6 (GALNT6), an initiating enzyme of mucin-type O-glycosylation, has been associated with breast cancer progression. However, whether GALNT6 exhibits subtype-specific expression and distinct histopathological localization patterns in breast cancer tissues has remained unclear. In this study, we performed subtype-stratified analyses of TCGA-BRCA RNA-seq data. We identified preferential GALNT6 upregulation in luminal A breast cancer, whereas expression was low in basal-like tumors and normal breast tissue. Gene co-expression network analysis further demonstrated that GALNT6-associated modules in luminal A breast cancer were enriched for estrogen receptor (ER) signaling, mammary epithelial development, and apical membrane-associated pathways, indicating close association with luminal epithelial transcriptional programs. To further characterize GALNT6 localization patterns in clinical tissues, we performed region-based histopathological and immunofluorescence analyses of luminal A breast cancer specimens. These analyses revealed architecture-dependent subcellular localization of GALNT6 associated with distinct Golgi organization patterns, showing apical/luminal-biased distribution in gland-forming regions and less polarized and more broadly distributed cytoplasmic localization in non-gland-forming tumor regions. E-cadherin was enriched at basolateral intercellular junctions, particularly in GALNT6-high tumors. Together, these findings identify GALNT6 as a luminal A-associated glycosylation-related marker linked to luminal epithelial transcriptional programs and architecture-dependent subcellular localization patterns in breast cancer.
Early melatonin supplementation partially delays gastrointestinal aging.
Sun T, Hu S, Xu T … +7 more , Wang S, Zhang Z, Wang Y, Sun H, Wu B, Yang S, Zhou D
Biochim Biophys Acta Mol Basis Dis · 2026 Jul · PMID 42385865 · Publisher ↗
Oxidative stress is a pivotal initiator of organismal aging. Targeted antioxidant interventions can effectively slow this process; however, the optimal timing for these interventions remains controversial. In this study,...
Oxidative stress is a pivotal initiator of organismal aging. Targeted antioxidant interventions can effectively slow this process; however, the optimal timing for these interventions remains controversial. In this study, we observed that with advancing age, the gastrointestinal tract of mice exhibited a progressive increase in oxidative stress, which was accompanied by a gradual decline in connexin 43 expression in the gastrointestinal mesothelium, without any detectable loss of mesothelial cells. Notably, the decrease in mesothelial connexin 43 was observed beginning at 16 months of age in mice, roughly equivalent to 50 years in humans, and occurred prior to the loss of enteric neurons and interstitial cells of Cajal. The administration of the antioxidant melatonin to 16-month-old mice significantly ameliorated oxidative stress, mitigated reduction in connexin 43, and attenuated degenerative alterations in the gastrointestinal tract, suggesting that connexin 43 expression may serve as a candidate morphological indicator for assessing gastrointestinal aging and the effectiveness of early antioxidant interventions in the clinic. Our findings demonstrate that the early stage of gastrointestinal aging is characterized by reversible functional impairments; timely and appropriate interventions during this period can partially delay gastrointestinal aging trajectory.
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