Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
CNDP2 drives renal tubular fibrosis in diabetic kidney disease via a sulfur-containing amino acids-mTOR signaling axis.
Li Y, Zheng QA, Chen YR … +9 more , Su C, Luo JY, Zheng ZJ, Xue JY, Wang Z, Chen YH, Liu P, Guo ZQ, Xue YM
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42276307 · Publisher ↗
BACKGROUND: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with proximal tubule fibrosis being a key pathological feature. Our previous study identified significant upregulation of cytosolic...
BACKGROUND: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with proximal tubule fibrosis being a key pathological feature. Our previous study identified significant upregulation of cytosolic nonspecific dipeptidase 2 (CNDP2) in the renal tubules of a DKD mouse model, yet its functional role remains unclear. OBJECTIVE: This study aimed to investigate the role of CNDP2 in renal tubular fibrosis during DKD, focusing specifically on the "sulfur-containing amino acids (SAAs) metabolism-mammalian target of rapamycin (mTOR)" signaling axis. METHODS: We employed integrated in vivo and in vitro models. Kidney- specific Cndp2 knockdown was achieved using an adeno-associated virus vector, and the CNDP2 inhibitor bestatin was used for pharmacological intervention. Renal function, fibrosis, the Ragulator-Rag GTPase-mTOR signaling pathway, amino acid profiles, and ultrastructural changes were assessed. A dietary intervention restricting SAAs was also applied. RESULTS: CNDP2 was specifically upregulated in renal tubules under DKD conditions. Both genetic knockdown and pharmacological inhibition of CNDP2 significantly improved renal function and attenuated fibrosis. Mechanistically, CNDP2 hydrolyzes dipeptides, leading to elevated levels of SAAs (cysteine/cystine). This promotes the activation of the Ragulator-Ras-related GTPase (Rag) complex, resulting in subsequent hyperactivation of mTOR signaling and driving tubular fibrosis. Notably, dietary restriction of SAAs similarly ameliorated DKD pathology. CONCLUSION: CNDP2 drives renal tubular fibrosis in DKD by activating mTOR signaling through disruption of SAAs metabolism. Our findings reveal a novel "CNDP2-SAAs-mTOR" pathway, identifying CNDP2 as a promising therapeutic target for DKD intervention.
STING-associated metabolic changes engage AMPK to amplify interferon signaling in Listeria-infected macrophages.
Chen S, Wang X, Duan Z … +6 more , Wang M, Qu X, Li J, Xia J, Xu Y, Xu L
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42276288 · Publisher ↗
Innate immune activation is tightly coupled to metabolic remodeling, yet how STING-associated signaling intersects with macrophage metabolism during bacterial infection remains incompletely understood. Here, using Lister...
Innate immune activation is tightly coupled to metabolic remodeling, yet how STING-associated signaling intersects with macrophage metabolism during bacterial infection remains incompletely understood. Here, using Listeria monocytogenes infection models, we show that infection is accompanied by increased glycolytic gene expression, glucose consumption, and lactate production in macrophages, and that STING deficiency attenuates these metabolic changes, whereas cGAS deficiency has a comparatively limited effect under our experimental conditions. Reduced glucose availability, 2-deoxy-d-glucose, and metformin enhanced AMPK activation, TBK1 phosphorylation, and IFN/ISG transcription, whereas Compound C treatment or Prkaa1 knockdown attenuated this enhancement. STING deficiency or acute STING inhibition reduced infection-associated glucose metabolic responses and limited the amplification of type I interferon-response gene expression under metabolic stress. Although the upstream mechanism by which STING regulates glucose metabolism remains to be fully defined, our findings support a model in which STING-associated metabolic changes and AMPK activity cooperate to enhance infection-induced interferon signaling during Listeria monocytogenes infection.
Identification and characterization of a novel Plakoglobin-binding protein highly expressed in the testes.
Yamashita M, Teshima K, Higuchi M … +6 more , Yamada R, Sawatsubashi S, Yokoyama A, Tomioka I, Ishiguro KI, Konishi H
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42276287 · Publisher ↗
1700020L24Rik was originally identified as one of the numerous mouse genes transcriptionally regulated by MEIOSIN (Meiosis initiator), but the function of its gene product has remained unknown. The human homolog of 17000...
1700020L24Rik was originally identified as one of the numerous mouse genes transcriptionally regulated by MEIOSIN (Meiosis initiator), but the function of its gene product has remained unknown. The human homolog of 1700020L24Rik is C17orf50, and both genes are highly expressed in the testes. In this study, we report that the protein encoded by 1700020L24Rik/C17orf50 is a Plakoglobin-binding protein. As its binding promotes the degradation of Plakoglobin, we named it Plakoglobin binding and degradation factor (PGBDF). PGBDF binds to the armadillo repeat of Plakoglobin via an α-helical region formed by approximately ten amino acids. PGBDF overexpression in cultured cells reduces the levels of Plakoglobin and induces cell aggregation accompanied by morphological changes. PGBDF localizes to both the cytoplasm and nucleus, and its subcellular distribution is regulated by phosphorylation. The inhibition of PGBDF phosphorylation by LiCl treatment promotes its cytoplasmic translocation, suggesting regulation by GSK3β and Wnt signaling. In mouse testes, PGBDF is predominantly expressed in interstitial regions. These findings suggest that PGBDF may contribute to the regulation of Plakoglobin levels and adhesion properties in testicular cells.
Caveolin-2 knockout suppresses the formation and progression of oral leukoplakia via lipid metabolism disruption.
Chen XJ, Bai YT, Jiang MJ … +2 more , Dong BJ, Zhou G
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42276203 · Publisher ↗
BACKGROUND: Caveolin-2 (CAV2) is a lipid droplet (LD)-associated protein. Its role in oral leukoplakia (OLK), an oral potentially malignant disorder, and the underlying lipid metabolism mechanisms remain unclear. METHODS...
BACKGROUND: Caveolin-2 (CAV2) is a lipid droplet (LD)-associated protein. Its role in oral leukoplakia (OLK), an oral potentially malignant disorder, and the underlying lipid metabolism mechanisms remain unclear. METHODS: CAV2 conditional knockout (cKO; CAV2) and control (Flox) C57BL/6 mice were used to establish OLK models via 4-nitroquinoline-N-oxide (4NQO). A subset received a high-fat diet (HFD). Oil red O staining, RNA sequencing, multiplex immunofluorescence (Ki-67, E-cadherin, Perilipin-1, FABP5), ELISA (acetyl-CoA), serum biochemistry (ALT, TG), and targeted GC-MS/MS fatty acid profiling were performed. RESULTS: CAV2 knockout significantly suppressed OLK progression, evidenced by reduced lesion diameter/number and attenuated pathological severity. HFD failed to rescue OLK progression. RNA-seq confirmed dysregulation of lipid transport, lipolysis, and fatty acid metabolism/biosynthesis. Targeted metabolomics revealed markedly attenuated carcinogen-induced fatty acid accumulation in cKO mice, with C18:2n6c (linoleic acid, LA) identified as the sole metabolite showing significant genotype-dependent reduction under 4NQO challenge. cKO mice exhibited downregulated Perilipin-1 and Ki-67, and upregulated FABP5 and E-cadherin. CAV2 knockout also induced lesion acetyl-CoA accumulation and systemic lipid metabolism abnormalities. CONCLUSIONS: CAV2 knockout inhibits OLK formation and progression by disrupting lipid metabolism homeostasis, including restriction of LA bioavailability. Exogenous fatty acid supplementation failed to rescue OLK progression or restore metabolic homeostasis, highlighting CAV2 as a potential therapeutic target.
The intratumoral microbiota: Orchestrating metabolic-immune crosstalk and shaping the therapeutic landscape in cancer.
Wang S, Liu Z, Jiang C … +3 more , Wei Y, Liu G, Pan Y
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42270015 · Publisher ↗
The intratumoral microbiota is now recognized as a key component of the tumor microenvironment, where it influences tumor metabolism, shapes immune activity, and modulates treatment responses. Microbial metabolites such...
The intratumoral microbiota is now recognized as a key component of the tumor microenvironment, where it influences tumor metabolism, shapes immune activity, and modulates treatment responses. Microbial metabolites such as short-chain fatty acids regulate pathways that control energy use in cancer cells and modify immune signaling within tumors. Microbial imbalance disrupts metabolic homeostasis and promotes immune escape, contributing to cancer progression and resistance to therapy. Specific taxa including Fusobacterium nucleatum drive distinct protumorigenic effects through metabolic and immunologic routes. Spatial heterogeneity of microbial colonization further defines metabolic gradients and immune niches that influence treatment efficacy. Advances in sequencing, multi-omics, and spatial profiling have clarified these interactions and identified microbial signatures with diagnostic and prognostic potential. Therapeutic strategies such as precision probiotics, engineered bacteria, and nanotechnology-based delivery systems offer avenues to target microbial metabolic pathways and enhance treatment response. Continued integration of microbiology, oncology, and bioinformatics will support translation of these findings into personalized cancer therapies.
Comparative analysis of nucleic acid delivery systems based on benzimidazolium surfactants: impact of auxiliary lipids on lipoplex internalization and functional gene delivery in cancer cells.
Kuznetsova DA, Kuznetsov DM, Lyubina AP … +5 more , Salakhieva DV, Ishkaeva RA, Nizameev IR, Voloshina AD, Zakharova LY
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42269847 · Publisher ↗
The design of effective non-viral nucleic acid delivery systems based on cationic amphiphilic compounds remains a major challenge in biomedical research. In this study, cationic benzimidazolium surfactants (BI-n) and cat...
The design of effective non-viral nucleic acid delivery systems based on cationic amphiphilic compounds remains a major challenge in biomedical research. In this study, cationic benzimidazolium surfactants (BI-n) and cationic liposomes composed of BI-n in combination with auxiliary lipids (DOPE, DOTAP, and cholesterol) were investigated and compared as potential nucleic acid carriers. Physicochemical and biological experiments were performed using a model double-stranded oligonucleotide, with additional transfection studies conducted using plasmid DNA. Both BI-n and liposomal systems effectively bound nucleic acids to form compact complexes (60-250 nm). Complex formation was driven primarily by electrostatic interactions, with additional contributions from hydrophobic and intercalation effects. The lipoplexes exhibited a predominantly spherical morphology, and showed high internalization efficiency in M-HeLa, A549, and HuTu 80 cancer cell lines. The N/P charge ratio was identified as a key factor regulating both cellular uptake and hemagglutination activity. Liposomal formulations containing auxiliary lipids demonstrated enhanced cellular internalization compared to surfactant-based systems. Importantly, transfection experiments using plasmid DNA (pEGFP-N2) revealed that BI-12-based systems enable functional nucleic acid delivery, resulting in efficient gene expression. BI-12 exhibited transfection efficiency comparable to a commercial reagent (Lipomaster 2000) and higher than that of DOTAP, while maintaining activity in the presence of serum. Notably, increased cellular uptake of liposomal systems did not result in improved transfection efficiency, highlighting the critical role of intracellular release. These findings demonstrate that benzimidazolium surfactants represent a promising platform for the development of non-viral delivery systems and provide insight into the structure-activity relationships governing nucleic acid transport.
Lipid droplet isolation as a novel platform for spectroscopic investigation of cargo modifications.
Chrabąszcz K, Panek A, Pogoda K
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42269831 · Publisher ↗
Lipid droplets (LDs) are dynamic organelles that coordinate lipid storage, trafficking, and metabolic adaptation under physiological and stress conditions. Despite their emerging role in cellular homeostasis, the molecul...
Lipid droplets (LDs) are dynamic organelles that coordinate lipid storage, trafficking, and metabolic adaptation under physiological and stress conditions. Despite their emerging role in cellular homeostasis, the molecular basis of treatment-induced lipid droplet remodeling remains insufficiently defined. Here, we combine lipid droplet isolation with label-free Raman spectroscopy to characterize biochemical and spectroscopic signatures associated with structural remodeling of isolated lipid droplets (iLDs) derived from normal Schwann cells and malignant peripheral nerve sheath tumor (MPNST) cells exposed to cannabidiol (CBD), ionizing radiation, and their combination. Our analysis reveals pronounced intrinsic spectral heterogeneity within iLD fractions and identifies treatment- and cell type-specific alterations in lipid composition, Raman spectral markers associated with acyl chain packing, and conformational order. Notably, stress-induced remodeling involves coordinated changes in lipid chain organization, highlighting lipid droplets as dynamic regulators of cellular metabolic adaptation. These findings provide molecular insight into lipid droplet-mediated stress responses and establish Raman-based profiling of isolated LDs as a powerful approach for investigating lipid remodeling mechanisms within isolated lipid droplet-enriched fractions. We further propose the Raman intensity ratio I₁₁₆₇/I₁₂₉₂ as a semiquantitative Raman-derived spectral index associated with stress-induced lipid remodeling and CBD-mediated radiosensitization.
Maternal vitamin A deficiency programs offspring visceral hypersensitivity through RARβ-COX-2/PGE2 signaling.
Tang M, Gou L, Bao W … +8 more , Lei J, Yang C, Hou F, Zhou Y, Yuan Y, Shen J, Chen Y, Tan M
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42269830 · Publisher ↗
Visceral hypersensitivity (VH) is regarded as a core pathophysiological mechanism in irritable bowel syndrome (IBS). Although maternal vitamin A deficiency (VAD) during pregnancy has been linked to gastrointestinal dysfu...
Visceral hypersensitivity (VH) is regarded as a core pathophysiological mechanism in irritable bowel syndrome (IBS). Although maternal vitamin A deficiency (VAD) during pregnancy has been linked to gastrointestinal dysfunction in offspring, its specific role in VH and the underlying mechanisms are not yet fully understood. This study aimed to explore the effects of maternal VAD on the development of VH in offspring and to assess the potential therapeutic role of postnatal vitamin A supplementation (VAS). Using a maternal VAD rat model, we observed that maternal VAD was associated with the development of VH in offspring, along with downregulated intestinal retinoic acid receptor β (RARβ) and activation of the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)/prostaglandin E2 receptor EP2 (EP2) axis in enteric glial cells (EGCs). These changes could be partially reversed by postnatal VAS. In a NaB-induced IBS model, VA intervention appeared to alleviate VH, gastrointestinal dysmotility, and diarrhea-like symptoms, possibly through suppression of the TLR4/MyD88/NF-κB pathway. In vitro experiments indicated that retinoic acid (RA), the active metabolite of VA, may inhibit TLR4/MyD88/NF-κB activation in EGCs, leading to reduced COX-2 expression and PGE2 synthesis. These findings suggest a nutritionally regulated mechanism linking maternal VA status to offspring VH and raise the possibility that the RA-RARβ axis may serve as a potential target for early nutritional interventions in IBS.
Determinants of MSC immunophenotypic plasticity: From canonical priming to emerging strategies for cancer and inflammatory therapies.
Tamimi R, Tafazzoli-Shadpour M, Vosough M
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42264158 · Publisher ↗
Mesenchymal stem cells (MSCs) exhibit remarkable plasticity, capable of adopting either pro-inflammatory (MSC1) or anti-inflammatory (MSC2) phenotypes in response to microenvironmental cues. This review explores their du...
Mesenchymal stem cells (MSCs) exhibit remarkable plasticity, capable of adopting either pro-inflammatory (MSC1) or anti-inflammatory (MSC2) phenotypes in response to microenvironmental cues. This review explores their dual role in cancer progression and suppression, immunomodulation of innate and adaptive immune cells, and therapeutic potential in inflammatory diseases. We systematically categorize and evaluate strategies to deterministically program MSC immunophenotypes, bridging canonical approaches (e.g., cytokines and chemokines, Toll-like receptors (TLRs) agonists, autophagy regulators, pharmacological agents, and bacterial components) with emerging non-canonical stimuli (e.g., natural and inorganic compounds, metal ions, engineered biomaterials, and patient-derived immunological components). These approaches provide new strategies to improve MSC-based therapies for cancer immunotherapy and regenerative medicine. While MSC2 phenotypes show promise in treating autoimmune and inflammatory disorders, MSC1 polarization presents opportunities for anti-tumor therapy, either alone or in combination with chemotherapy. However, context-dependent effects of stimuli underscore the need for precise mechanistic understanding. Challenges remain in standardizing protocols, optimizing dosing regimens, and ensuring clinical translation. Future research should focus on elucidating signaling crosstalk, developing GMP-compatible preconditioning methods, and validating combination therapies in complex tumor microenvironment (TME) models. By integrating emerging technologies-such as single-cell analysis and biomaterial engineering-with established approaches, this review highlights pathways toward personalized MSC-based therapies, bridging the gap between experimental innovation and clinical application in inflammation, cancer, and tissue repair.
Short-lived versus long-lived lncRNAs: RNA stability as a determinant of regulatory function.
Tani H
Biochim Biophys Acta Gene Regul Mech · 2026 Jun · PMID 42264142 · Publisher ↗
Long non-coding RNAs (lncRNAs) are classified by sequence, genomic context, and subcellular localization, yet RNA stability remains an underexplored axis of functional classification. Genome-wide profiling by BRIC-seq id...
Long non-coding RNAs (lncRNAs) are classified by sequence, genomic context, and subcellular localization, yet RNA stability remains an underexplored axis of functional classification. Genome-wide profiling by BRIC-seq identified hundreds of lncRNAs with half-lives below 4 h, termed Short-Lived noncoding Transcripts (SLiTs), while Long-Lived RNAs (LL-RNAs) that persist for years in post-mitotic cells define the opposite extreme. We argue that stability is an underappreciated determinant of lncRNA function: short-lived lncRNAs act as dynamic molecular sensors enabling rapid transcriptional responses, whereas long-lived lncRNAs may serve as structural scaffolds maintaining chromatin architecture in post-mitotic cells. We review the molecular mechanisms of lncRNA turnover, the functional consequences of stability in disease, and propose RNA half-life as a candidate additional axis-a working "fifth code"-complementing sequence, structure, modification, and localization for predicting non-coding RNA function. We emphasize that this proposal currently rests largely on correlative associations between half-life and functional class, that the "fifth code" is best understood as an integrated readout of upstream regulatory inputs rather than a primary independent determinant, and that the manuscript explicitly distinguishes experimentally established observations from hypothesis-driven interpretations throughout.
Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
Ahn A, Hong S, Brischigliaro M … +2 more , Fontanesi F, Barrientos A
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42263953 · Full text
Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this c...
Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this context, mitochondrial mRNAs function not merely as templates for translation but as structured molecules whose folding landscape contributes to multiple stages of gene expression. Recent advances in chemical probing, mutational profiling, and mitoribosome profiling have begun to disclose the human mitochondrial mRNA structurome in its native organellar context, revealing a transcriptome that is broadly accessible yet punctuated by localized structural elements and alternative conformational states. These studies indicate that RNA structure contributes to translation initiation on leaderless transcripts, elongation kinetics, translational coupling across bicistronic junctions, and dynamic remodeling during membrane protein synthesis. They also highlight the role of RNA-binding proteins, including LRPPRC-SLIRP and related factors, in maintaining a translation-competent folding environment. In this review, we discuss the structural organization of mitochondrial mRNAs, the experimental approaches that enabled its analysis, and emerging mechanistic links between RNA folding, translational regulation, and respiratory chain biogenesis. We further discuss how alterations in mt-mRNA structure may represent an underappreciated determinant of mitochondrial disease and consider implications for future diagnostic and therapeutic strategies.
Absence of EOGT precludes defective development in fringe-null mouse intestine.
Nauman M, Zhang J, Stanley P
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42263921 · Publisher ↗
Identifying biological roles for glycosyltransferases is a continuing challenge and important for defining morbidities associated with congenital disorders of glycosylation. Here we investigate the consequences to intest...
Identifying biological roles for glycosyltransferases is a continuing challenge and important for defining morbidities associated with congenital disorders of glycosylation. Here we investigate the consequences to intestinal development of conditionally deleting Lfng alone or Lfng, Mfng and Rfng together in a mixed or Eogt-null genetic background. Each Fringe transfers N-acetylglucosamine (GlcNAc) to fucose (Fuc) attached to Ser or Thr by POFUT1 in a consensus sequence found in certain epithelial growth factor-like (EGF) repeats. EOGT transfers GlcNAc directly to Ser/Thr in a separate consensus sequence of an EGF repeat. Notch receptors and Notch ligands contain the largest number of EGF repeats with consensus sites for these O-glycans. Conditional deletion of Pofut1 in mouse intestine causes similar developmental defects to deletion of Notch1 and Notch2 or Dll1 and Dll4. LFNG also contributes to optimal Notch signaling in mouse intestine. In this work, we generated Lfng[F/F]:Villin-Cre and Lfng[F/F]Mfng[-/-]Rfng[-/-]:Villin-Cre mice in which extension of O-Fuc on EGF repeats was respectively inhibited or prevented in intestinal epithelium. Conditional deletion of either Lfng alone or all three Fringe activities together led to defective intestinal development with a marked increase in goblet and Paneth cells, increased crypt width and reduced villus length. Unexpectedly, in mice globally lacking EOGT, conditional inactivation of the three Fringe genes did not lead to defective intestinal development. Thus, the absence of EOGT prevented disruption of development in Fringe-null intestine, identifying a novel role for EOGT in regulating intestinal development.
Involvement of immunomodulators in the development of cancer vaccines.
Bibi R, Swayamsiddhi, Saishree S … +3 more , Sobti M, Reddy S, Sarkar K
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263891 · Publisher ↗
Previous research shows that cancer vaccines hold great potential as immunotherapeutic agents which activate the body's tumor-cell elimination powers through immune recognition. Cancer vaccines encounter restricted succe...
Previous research shows that cancer vaccines hold great potential as immunotherapeutic agents which activate the body's tumor-cell elimination powers through immune recognition. Cancer vaccines encounter restricted success because of three limiting factors that include immunosuppressive tumor microenvironment (TME) dynamics and deficient antigen presentation and tumor immune evasion methods. Immunomodulators function as vital instruments which help patients overcome vaccination resistance barriers in addition to strengthening vaccine-generated immunity. The review investigates how different immunomodulatory agents such as cytokines and checkpoint inhibitors as well as TLR agonists and STING pathway activators, oncolytic viruses enhance the effectiveness of cancer vaccines. The immune response derives additional advantages from these agents. They enhance antigen presentation, activate T cells, counteract immune suppression, and improve the structural integrity of the tumor microenvironment (TME). The review examines modern treatment developments that include individualized neoantigen vaccines and nanoparticle delivery vehicles alongside microbiome modification strategies as promising methods for customized effective cancer treatments. Although cancer vaccines face obstacles from toxicity and heterogeneous tumors and limitations in manufacturing there is potential to combine them with immunomodulators for creating sustainable and specific cancer treatments. Further research along with innovative work needs to occur to develop clinically effective patient-specific treatments from existing therapeutic breakthroughs.
Piezo1 mediates hypoxia and mineralization in cementoblasts.
Wang Y, Wang L, Ruf S … +2 more , Staszyk C, Groeger S
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263890 · Publisher ↗
Orthodontically induced inflammatory root resorption (OIIRR) is a common complication associated with excessive compressive force during orthodontic treatment, leading to irreversible cementum destruction. However, the c...
Orthodontically induced inflammatory root resorption (OIIRR) is a common complication associated with excessive compressive force during orthodontic treatment, leading to irreversible cementum destruction. However, the cellular and molecular mechanisms underlying this process remain unclear. This study aimed to investigate the role of the mechanosensitive ion channel Piezo1 in regulating cementoblast function under mechanical stress. Cementoblasts (OCCM-30) were subjected to 1 g/cm of compressive force, and global gene expression was analyzed via RNA sequencing, revealing 6932 differentially expressed genes. Compressive force upregulated the expression of HIF-1α and its downstream angiogenesis-related genes (Vegf, Angpt1, Angptl4), while significantly downregulating osteogenic markers such as RUNX2 and SP7, leading to suppressed mineralization and calcium nodule formation. Activation of Piezo1 using the agonist Yoda1 mimicked the effects of compressive force, whereas inhibition by GSMTX4 reversed them. Interestingly, depletion of extracellular calcium did not affect these outcomes, suggesting that Piezo1 acts independently of calcium influx in this context. Moreover, Piezo1 activation and compressive force co-upregulated LIM and cysteine-rich domains 1 (LMCD1) and downregulated Periostin (POSTN), both of which were identified as novel downstream effectors of Piezo1 signaling. These changes were also reversed by Piezo1 inhibition. In conclusion, compressive force impairs cementoblast mineralization while enhancing hypoxia and angiogenic pathways through Piezo1 activation. LMCD1 and POSTN may serve as new molecular targets for understanding and potentially preventing OIIRR. This study provides important insights into the mechanotransduction mechanisms in cementoblasts and identifies Piezo1 as a key regulator linking mechanical stimuli to pathological root resorption.
WTAP-mediated m6A modification of UBE2K drives the malignant progression of gastric cancer.
Guo J, Zhang Z, Sun Y … +13 more , Yu Z, Zhu Q, Yuan Z, Hu S, Xia Y, Wu Q, Zhang G, Liu X, Hu X, Cui D, Huang D, Xu Q, Li S
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263889 · Publisher ↗
BACKGROUND: Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Ubiquitin-conjugating enzyme E2 K (UBE2K), defined as an E2, is involved in various cellular processes. N6-methylad...
BACKGROUND: Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Ubiquitin-conjugating enzyme E2 K (UBE2K), defined as an E2, is involved in various cellular processes. N6-methyladenosine (m6A) is one of the most abundant subtypes of RNA modifications. However, the systematic role of UBE2K and whether UBE2K undergoes an m6A modification in GC remain unknown. METHODS: The expression and prognosis of UBE2K in GC were analyzed through an online database. RT-qPCR, western blot and IHC were used to test the expression of UBE2K in GC tissues and cells. CCK-8, colony formation, transwell, wound healing and sphere formation assays were conducted to explore UBE2K's function in vitro. The subcutaneous mouse model was generated to validate UBE2K's role in tumorigenesis. RNA immunoprecipitation and RNA stability experiment were applied to investigate the molecular mechanism of UBE2K. RESULTS: Higher expression of UBE2K was found in GC tissues and predicted worse prognosis. UBE2K knockdown suppressed the malignant progression of GC cells both in vitro and in vivo. Mechanistically, we found that UBE2K was regulated by m6A modification. WTAP was further revealed as the m6A writer of UBE2K to enhance UBE2K RNA stability. Finally, functional rescue experiments showed that silencing WTAP reversed the oncogenic effects of UBE2K overexpression on GC cells, whereas WTAP attenuated the suppression of GC cells induced by UBE2K knockdown. CONCLUSION: Our findings indicate WTAP-mediated m6A modification upregulates UBE2K and the WTAP/UBE2K axis facilitates GC progression, suggesting a potential therapeutic target for GC treatment.
Ajugol attenuates acute gouty arthritis by enhancing mitophagy to suppress chondrocyte pyroptosis.
Zhang Y, Liu Y, Xie W … +5 more , Fu Y, Liu Z, Yin Q, Gao Z, Liu W
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263888 · Publisher ↗
Gouty arthritis (GA), triggered by monosodium urate (MSU) crystal deposition, is closely associated with oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome-mediated pyroptosis. This study combined networ...
Gouty arthritis (GA), triggered by monosodium urate (MSU) crystal deposition, is closely associated with oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome-mediated pyroptosis. This study combined network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation to elucidate the mechanism by which the iridoid glycoside ajugol alleviates GA. Network pharmacology analyses identified the PI3K/AKT/mTOR pathway as a key regulatory axis, and docking results revealed stable binding of ajugol to PI3K, AKT, and mTOR. In LPS/MSU-stimulated human chondrocytes, ajugol significantly restored cell viability, reduced LDH release, and preserved extracellular matrix integrity by increasing Collagen II and Aggrecan expression while decreasing MMP-3 levels. Ajugol markedly inhibited the expression of NLRP3, ASC, caspase-1, and GSDMD-N, reduced the secretion of IL-1β, IL-18, IL-6, and TNF-α, and decreased caspase-1 activity and membrane pore formation, indicating that ajugol suppresses pyroptosis through enhanced mitophagy. The mitophagy inhibitor cyclosporin A (CsA) significantly weakened ajugol-induced mitophagy activation and pyroptosis inhibition, confirming that mitophagy plays a pivotal role in its protective effects. Mechanistically, ajugol inhibited PI3K/AKT/mTOR phosphorylation, upregulated PINK1, Parkin, and LC3-II/LC3-I while reducing p62, thereby activating PINK1/Parkin-dependent mitophagy. PI3K agonist 740YP partially reversed ajugol's effects, whereas PI3K inhibitor LY294002 mimicked them, verifying pathway involvement. In MSU-induced GA mice, oral ajugol administration alleviated joint swelling, reduced inflammatory cytokines and NLRP3 expression, preserved cartilage integrity, and restored autophagy via PI3K/AKT/mTOR suppression. Collectively, ajugol alleviates inflammation and cartilage damage by suppressing the PI3K/AKT/mTOR pathway, activating mitophagy, and inhibiting pyroptosis, providing a promising mitochondrial-targeted therapeutic strategy for gouty arthritis.
SPDEF promotes clear cell renal cell carcinoma progression by transcriptionally activating ELOVL2-mediated lipid metabolic reprogramming.
Zhang P, Yu W, Luo H … +7 more , Wang D, Li M, Wang T, Guo Y, Xiong W, Gong B, He Y
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263887 · Publisher ↗
BACKGROUND: Characterized by cytoplasmic lipid accumulation and fatty-acid metabolic reprogramming, clear cell renal cell carcinoma (ccRCC) is closely related to tumor progression and invasion. The impact of SPDEF, an ET...
BACKGROUND: Characterized by cytoplasmic lipid accumulation and fatty-acid metabolic reprogramming, clear cell renal cell carcinoma (ccRCC) is closely related to tumor progression and invasion. The impact of SPDEF, an ETS transcription factor, in ccRCC and its involvement in lipid metabolism remain unclear. METHODS: SPDEF expression and prognostic relevance were analyzed using TCGA-KIRC data and validated in ccRCC tissues and cell lines. Functional experiments were conducted to evaluate influence on cell proliferation, migration, lipid metabolism, and apoptosis. Regulatory interactions with ELOVL2 were examined via transcriptomic analysis, dual-luciferase reporter assays, ChIP-qPCR, and site-directed promoter mutagenesis. RESULTS: SPDEF was significantly overexpressed and closed to higher TNM stage and unfavorable survival. The higher expression of SPDEF enhanced malignant phenotypes, increased lipid accumulation, and impeded apoptotic processes. Mechanistically, SPDEF bound to the -141 bp site of the ELOVL2 promoter, thereby activating its transcription; mutation of this site abolished activation. Altering ELOVL2 expression partially rescued or mimicked SPDEF-driven phenotypes. CONCLUSIONS: SPDEF acts as an oncogenic transcriptional activator in ccRCC by directly upregulating ELOVL2, thereby driving lipid metabolic reprogramming and tumor progression. These findings provide mechanistic insight into the SPDEF-ELOVL2 axis in lipid-associated ccRCC progression, while its clinical and translational relevance requires further validation in larger patient cohorts and clinically relevant models.
MAZ-driven MRPL11 links mitochondrial homeostasis to AKT/mTOR signaling and promotes pancreatic ductal adenocarcinoma progression.
Huang S, Liu X, Ruan Z … +4 more , Hou G, Liao Y, Gu D, Xiong W
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263886 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, owing to late diagnosis, rapid progression, and resistance to therapy. Here, we identify mitochondrial ribosomal protein L11 (MRPL11) a...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, owing to late diagnosis, rapid progression, and resistance to therapy. Here, we identify mitochondrial ribosomal protein L11 (MRPL11) as a novel oncogenic driver of PDAC. Multi-omics and survival analyses revealed that MRPL11 is markedly upregulated in PDAC tissues and cell lines, and its elevated expression predicts poor overall survival (OS) and disease-free survival (DFS). Functional assays demonstrated that MRPL11 promotes proliferation, migration, invasion, and spheroid growth, whereas its depletion induces G1/S arrest, apoptosis, and sensitizes cells to parthenolide (PTL). Mechanistically, MRPL11 preserves mitochondrial homeostasis by maintaining ATP production, membrane potential, and oxidative phosphorylation (OXPHOS), while limiting the accumulation of reactive oxygen species (ROS). In addition, MRPL11 activates the AKT/mTOR pathway, and its transcription is directly regulated by the MYC-associated zinc finger protein (MAZ). Rescue experiments confirmed that the MAZ-MRPL11 axis drives PDAC aggressiveness through AKT/mTOR activation. In vivo, MRPL11 knockdown significantly suppressed xenograft tumor growth and enhanced apoptosis. Collectively, these findings establish MRPL11 as a critical link between mitochondrial regulation and oncogenic signaling, underscoring its potential as a prognostic biomarker and a candidate molecule for further therapeutic investigation in PDAC.
Obesity history exacerbates liver macrophage-mediated fibrosis via IGFBP7.
Soedono S, Chun S, Vo DHN … +5 more , Julietta V, Chang J, Oh BC, Lumeng CN, Cho KW
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42263885 · Publisher ↗
Weight regain is a frequent outcome after lifestyle-induced weight loss and is closely linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which prior...
Weight regain is a frequent outcome after lifestyle-induced weight loss and is closely linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which prior obesity predisposes to metabolic dysfunction-associated steatohepatitis (MASH) development remain unclear. This study investigates how obesity history influences hepatic steatosis and fibrosis during weight regain. A diet-switch model was used to establish obesity, weight loss (WL), weight regain (RCHFD), and short-term obesity (STHFD) conditions, enabling comparisons between groups with and without prior obesity. Hepatic fibrosis during weight regain was induced using carbon tetrachloride (CCl) alongside a second high-fat diet challenge. Obesity history exacerbated hepatic fibrosis during weight regain in the CCl model, accompanied by pronounced liver macrophage (Mφ) activation. Even without CCl treatment, RCHFD mice displayed worsened hepatic steatosis and fibrosis compared to mice without prior obesity, associated with sustained liver Mφ accumulation. Despite the resolution of steatosis and inflammation after weight loss, Mφ persistence coincided with continuous hepatic stellate cell (HSC) activation, as evidenced by elevated alpha-smooth muscle actin (α-SMA) expression. Co-culture studies revealed that liver Mφs from WL mice could activate HSCs, recapitulating the effects of obesity. Mechanistically, IGFBP7 was upregulated in liver Mφs during both obesity and WL, and its secretion mediated HSC activation. These findings demonstrate that obesity history accelerates MASH progression during weight regain through a macrophage/IGFBP7/HSC axis. Targeting IGFBP7 may represent a potential therapeutic approach to prevent fibrosis progression in individuals with a history of obesity.
Neuroprotection by lactate in Parkinson's disease: A novel anti-inflammatory mechanism via 14-3-3 protein lactylation.
Zhang Q, Liu M, Cao WJ … +4 more , Zou W, Zhang P, Tang YY, Tang XQ
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42252031 · Publisher ↗
BACKGROUND: Novel therapeutic strategies for Parkinson's disease (PD) are urgently needed. Neuroinflammation is a critical driver of disease progression and represents a promising target for intervention. Emerging eviden...
BACKGROUND: Novel therapeutic strategies for Parkinson's disease (PD) are urgently needed. Neuroinflammation is a critical driver of disease progression and represents a promising target for intervention. Emerging evidence highlights lactate as a signaling metabolite that regulates inflammatory responses through protein lactylation. Given the involvement of 14-3-3 proteins in PD pathogenesis, we investigated whether lactate confers neuroprotection by promoting 14-3-3 lactylation and modulating neuroinflammatory signaling in PD. METHODS: A rat model of PD was induced by subcutaneous injection of Rotenone (ROT) into the dorsal cervical region. Lactate was administered intracerebroventricularly. Motor function was assessed using open field, grid, and suspension tests. TH-positive neurons in the substantia nigra were evaluated by immunohistochemistry. The lactylation of 14-3-3 proteins and their interaction with NLRP3 were examined by co-immunoprecipitation (Co-IP). Mitochondrial localization of GSDMD was visualized by immunoelectron microscopy. The cytosolic mtDNA was assessed using qPCR. NLRP3 inflammasome components, the cGAS-STING pathway, and mitochondrial GSDMD were analyzed by western blotting. Levels of inflammatory cytokines and cGAMP were quantified by ELISA. RESULTS: Lactate ameliorated motor deficits and dopaminergic neuron loss in ROT-treated rats. Lactate increased 14-3-3 lactylation and enhanced 14-3-3 binding to NLRP3, accompanied by reduced NLRP3 inflammasome activation, attenuated GSDMD-associated mitochondrial injury, decreased cytosolic mtDNA levels, and suppressed cGAS-STING pathway activation. CONCLUSION: Lactate exerts neuroprotective effects in PD through a mechanism associated with enhanced 14-3-3 lactylation, reduced NLRP3/GSDMD pathway activation, attenuated GSDMD-associated mitochondrial injury, decreased cytosolic mtDNA levels, and suppression of cGAS-STING signaling.
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