Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
Fetal bovine serum enhances recombinant protein secretion and stability in Pichia pastoris.
Nguyen KL, Vierra C, Vang D … +9 more , Amer N, Yee C, Vue T, Afzal HM, Nguyen FT, Elnokrashy N, Lin-Cereghino J, Thor D, Lin-Cereghino GP
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42248337 · Publisher ↗
BACKGROUND: Komagataella phaffii, formerly known as Pichia pastoris, is a methylotrophic yeast employed as a recombinant protein factory for academic and industrial purposes. Despite its advantages, some recombinant prot...
BACKGROUND: Komagataella phaffii, formerly known as Pichia pastoris, is a methylotrophic yeast employed as a recombinant protein factory for academic and industrial purposes. Despite its advantages, some recombinant proteins, which are engineered to be secreted, are retained intracellularly and subject to degradation. Serendipitously, we discovered that fetal bovine serum (FBS) improved the secretion of several proteins. When a P. pastoris strain expressing enhanced green fluorescent protein (eGFP) was grown with FBS, western analysis revealed a 2-3 fold increased level of eGFP secretion as well as the induction of an upper molecular band (30 kD) in addition to the expected band (26.8 kD). FBS protected the C-terminus of eGFP from degradation, and the alterations to this upper molecular weight variant were triggered intracellularly by an FBS component that was most likely not a protein. METHODS: To elucidate the mechanisms behind the production of the novel recombinant protein variant, we utilized site-directed mutagenesis and mass spectrometry. RESULTS: Through these strategies, we were able to localize posttranslational modifications to the C-terminus associated with FBS treatment. Analysis of the intracellular lysate revealed proteomic alterations, suggesting that genes involved in translation, trafficking, stress response and energetics were key players in FBS's effect on the P. pastoris secretion mechanism through interaction with eGFP's C-terminus. GENERAL SIGNIFICANCE: Our study suggests that C-terminal degradation may affect other recombinant proteins produced in P. pastoris, a problem that may be resolved by FBS.
Inositol biosynthesis is inversely regulated by glycolytic activity.
Onu CJ, Adu M, Jabbar D … +4 more , Ezumel E, Schmidtke MW, Saiardi A, Greenberg ML
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42242622 · Publisher ↗
Inositol is an essential metabolite required for membrane biogenesis, cell signaling and trafficking, and gene expression. Its importance is underscored by the fact that inositol depletion leads to death in eukaryotic ce...
Inositol is an essential metabolite required for membrane biogenesis, cell signaling and trafficking, and gene expression. Its importance is underscored by the fact that inositol depletion leads to death in eukaryotic cells ranging from yeast to human. Perturbation of inositol homeostasis is implicated in numerous human disorders. In yeast, inositol is synthesized de novo from glucose-6-phosphate (G-6-P) through a two-step pathway controlled by the rate-limiting enzyme myo-inositol phosphate synthase (MIPS), encoded by INO1. INO1 expression is tightly controlled by the Henry regulatory circuit in response to inositol and by the Reg1-Snf1 pathway in response to glucose. As both inositol synthesis and glycolysis utilize the same precursor, G-6-P, the current study tested the hypothesis that inositol synthesis is regulated by glycolytic activity. Genetic and pharmacological approaches were used to alter glycolysis. Inositol synthesis was determined by liquid chromatography mass spectrometry analysis of [U-C]-glucose incorporation into inositol and by assaying INO1 mRNA and MIPS protein expression. In rho0 cells and wild type cells treated with the electron transport inhibitor potassium cyanide, both of which exhibit increased glycolytic activity, inositol levels were reduced by 47.5% and 57.9%, respectively, compared to controls. INO1 mRNA and MIPS protein levels were also decreased in these cells. The effect of downregulation of glycolysis was determined using the humanized yeast strain HHK2, which expresses a decreased rate of glycolysis due to the less active human hexokinase. Consistent with our hypothesis, HHK2 cells exhibited a 41.5% increase in inositol synthesis. Dysregulation of inositol synthesis did not affect glycolysis. These results identify altered glycolytic activity as a mechanism of inositol regulation and demonstrate the role of metabolic crosstalk in controlling these biochemical pathways.
Trans-10, cis-12 conjugated linoleic acid modulates offspring hepatic lipid metabolism by activating AMPK pathway associated with altered gut microbiota.
Yu S, Lu H, Rao Y … +3 more , Wang B, Cui S, Gou K
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42242621 · Publisher ↗
OBJECTIVE: Trans-10, cis-12 conjugated linoleic acid (t10c12-CLA) can affect lipid metabolism, leading to weight loss and attracting widespread attention. However, its suitability for use in lactating mothers remains unc...
OBJECTIVE: Trans-10, cis-12 conjugated linoleic acid (t10c12-CLA) can affect lipid metabolism, leading to weight loss and attracting widespread attention. However, its suitability for use in lactating mothers remains unclear. A transgenic mouse, named Pai (homozygous) and Pai/wt (heterozygous), capable of producing endogenous t10c12-CLA was successfully established. METHODS: In this study, embryo transfer technology was utilized to transplant embryos of wild-type (wt) mice into the transgenic mice, in order to investigate the effects of t10c12-CLA on biometric and reproductive parameters. RESULTS: Embryo transfer efficiency remained unchanged following the procedure. The male-to-female ratio of offspring in Pai/wt group was significantly higher than that in wt and Pai groups. Additionally, the birth weight, 21-day body weight, serum glucose level and triglyceride level of pups in Pai group were significantly lower than those in wt group. Simultaneously, the Pai pups exhibited modulated gut microbiota composition and regulated metabolic profiles in white adipose tissue and liver. Further investigations in liver tissue and HepG2 cells revealed that these effects featured suppressed lipogenesis (FASN, ChREBP), enhanced fatty acid oxidation (CPT1A) through activation of AMPK pathway in liver. CONCLUSIONS: Maternal t10c12-CLA could suppress lipogenesis and lower lipid levels by activating the AMPK pathway, and alter the composition of gut microbiota, thereby impacting offspring lipid metabolism.
Shaping breast cancer progression in obesity: Insights from advanced models and omics tools.
Emma R, Sergi V, Scordamaglia D … +4 more , Scollo P, Clarke RB, Malaguarnera R, De Francesco EM
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42242589 · Publisher ↗
Obesity is a negative prognostic factor in BC, a heterogeneous and complex disease representing the leading cause of mortality from female cancer. Within the breast tumour microenvironment (TME), adipocytes, fibroblasts,...
Obesity is a negative prognostic factor in BC, a heterogeneous and complex disease representing the leading cause of mortality from female cancer. Within the breast tumour microenvironment (TME), adipocytes, fibroblasts, immune cells and the extracellular matrix are aberrantly activated in obesity, leading to inflammatory responses, together with hormonal and metabolic changes, and activation of oncogenic pathways that facilitate disease progression. To fully grasp the metabolic complexity and heterogeneity of obese BC patients, proper experimental models, able to mimic the aberrant interactions occurring within the obese breast TME, are required. Herein, we first present the most recent findings on the players involved in the remodelling of the breast TME during obesity. Next, we highlight the main advanced preclinical models used to investigate the interaction between obesity and BC, including immunocompetent and immunodeficient in vivo systems, as well as advanced 3D in vitro and ex vivo models. We focus on the integration of these models with advanced omics techniques, such as transcriptomics, proteomics and metabolomics, toward a more systematic and dynamic view of the obesity-BC link. Finally, we discuss the current limitations of available models and the future prospects to advance knowledge in the field.
Interaction of venlafaxine and its major metabolite O-desmethylvenlafaxine with phosphatidylcholine bilayer.
Le TTQ, Ngo DNT, Ho TH … +2 more , Huynh LK, Nguyen TT
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42242524 · Publisher ↗
Venlafaxine (VLX) and its active metabolite O-desmethylvenlafaxine (ODV) must partition into lipid membranes before reaching their membrane-embedded transporter targets. The principal active metabolite, ODV, differs from...
Venlafaxine (VLX) and its active metabolite O-desmethylvenlafaxine (ODV) must partition into lipid membranes before reaching their membrane-embedded transporter targets. The principal active metabolite, ODV, differs from VLX by the removal of a methyl group and is itself marketed as an antidepressant. Here, we combined long-timescale all-atom molecular dynamics simulations with experimental membrane partitioning measurements to investigate how demethylation, stereochemistry, and drug concentration influence their interactions with phosphatidylcholine bilayers. All drug species spontaneously partitioned into the lipid-water interface and stabilized at ∼1.4 nm from the bilayer center while maintaining a conserved amphipathic orientation. Free-energy calculations revealed similar interfacial free-energy minima of approximately -20 kJ mol for both compounds, whereas the energetic penalty for translocation toward the bilayer core exceeded 40 kJ mol. Demethylation of VLX lowered the energetic barrier for membrane insertion without altering the thermodynamically favored interfacial state, indicating that ODV accesses the membrane interface more efficiently while preserving comparable equilibrium membrane affinity. Experimental second-derivative UV-Vis spectroscopy further confirmed similar membrane partitioning for VLX and ODV. At low drug concentrations, membrane structure remained largely unperturbed following insertion. In contrast, elevated drug loading induced cooperative membrane perturbation characterized by lateral bilayer expansion, membrane thinning, and reduced acyl-chain order, with these effects consistently more pronounced for ODV. Together, these findings identify the lipid bilayer under studied conditions as a dynamically adaptive kinetic interface rather than a passive equilibrium reservoir, suggesting that functional differences between VLX and ODV arise primarily from differences in interfacial accessibility and subsequent protein-specific interactions rather than nonspecific membrane affinity alone.
Fluorescence readouts of KL-induced changes in lipid order and fluidity in surfactant-like bilayers relevant to ARDS and COVID-19 lung injury.
Braide-Moncoeur O, Tran N, Yi M … +2 more , Long JR, Fanucci GE
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42242523 · Full text
KL, a 21-residue mimetic of the C-terminus of surfactant protein B, is effective in treating infant respiratory distress syndrome (RDS). It works by reducing alveolar surface tension and improving oxygen exchange. Here,...
KL, a 21-residue mimetic of the C-terminus of surfactant protein B, is effective in treating infant respiratory distress syndrome (RDS). It works by reducing alveolar surface tension and improving oxygen exchange. Here, we use steady-state fluorescence measurements to probe how KL modulates bilayer order and organization in pulmonary surfactant-like lipid mixtures with varying acyl chain saturation. We show how fluorescence-based methods can distinguish between a more surface-associated and a more deeply inserted mode of interaction of KL in phospholipid membranes with varying acyl chain saturation. Specifically, in saturated liposomes with a tail-labeled pyrene analog, KL addition decreases excimer-to-monomer (Ie/Im) ratios and produces larger changes in the steady-state anisotropy of rhodamine-labeled lipids, consistent with reduced lipid mobility and peptide-induced changes in bilayer packing, and is qualitatively consistent with previous ssNMR/EPR studies of KL. Conversely, fluorescence results for unsaturated liposomes show smaller changes in Ie/Im and anisotropy, suggesting greater interfacial interaction between KL and a more modest impact on bilayer order. Increasing concentrations of KL4 in unsaturated lipids result in a notable decrease in rhodamine headgroup emission intensity, suggesting local environmental shifts or collisional quenching, consistent with a more surface-proximal peptide. Overall, these fluorescence readouts are sensitive to KL-induced changes in bilayer order, lipid dynamics, and lateral organization, but do not, by themselves, define peptide orientation or insertion depth. These assays require minimal sample and simple equipment, making them practical for monitoring how KL and similar surfactant mimics influence bilayer behavior across different lipid compositions and for screening lipid and peptide combinations in future models of healthy and diseased surfactant relevant to neonatal RDS and adult ARDS, including COVID-19.
Consequences of defective mitochondrial protein import: From targeting signals to pathology.
Cornejo MC, Lee SCS, Smith S … +1 more , Koehler CM
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42242522 · Publisher ↗
Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coor...
Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.
HIF-2α/TRIB3/PARP1 axis promotes progression by orchestrating DNA repair in clear cell renal cell carcinoma.
Li W, Xu Q, Song J … +4 more , Song W, Fei M, Zhang K, Yan Z
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42242437 · Publisher ↗
In clear cell renal cell carcinoma (ccRCC), aberrant accumulation of hypoxia-inducible factor-2α (HIF-2α) due to VHL gene mutation is a central event driving tumorigenesis and progression. Although DNA damage is a hallma...
In clear cell renal cell carcinoma (ccRCC), aberrant accumulation of hypoxia-inducible factor-2α (HIF-2α) due to VHL gene mutation is a central event driving tumorigenesis and progression. Although DNA damage is a hallmark of renal cancer development, it remains unclear whether and how HIF-2α regulates downstream targets to modulate the DNA damage and repair process. Here, we demonstrate that HIF-2α transcriptionally activates TRIB3 expression. Further we found that TRIB3 interacts with PARP1, a key DNA repair protein, and enhances nuclear PARP1 stability by inhibiting its K63-linked polyubiquitination, thereby promoting the DNA repair capacity of ccRCC cells. Both in vitro and in vivo, the HIF-2α inhibitor belzutifan (PT2977) effectively suppressed this signaling axis and reversed the tumor-promoting effects caused by PARP1 overexpression. Collectively, our findings elucidate a critical role for the HIF-2α/TRIB3/PARP1 axis in ccRCC progression, revealing potential therapeutic targets and rational combination strategies for this disease.
Huaier counteracts sorafenib resistance in hepatocellular carcinoma by activating NCOA4-mediated ferritinophagy to induce ferroptosis via modulation of iron and lipid metabolism.
Zhang Z, Feng Y, Mu Z … +2 more , Zhang W, Zhou F
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42242436 · Publisher ↗
Resistance to molecular-targeted agents, represented by sorafenib (SOR), poses a major challenge in the treatment of hepatocellular carcinoma (HCC). Huaier (HUA), a traditional Chinese medicine used as an adjuvant cancer...
Resistance to molecular-targeted agents, represented by sorafenib (SOR), poses a major challenge in the treatment of hepatocellular carcinoma (HCC). Huaier (HUA), a traditional Chinese medicine used as an adjuvant cancer therapy, has demonstrated favorable efficacy in clinical practice for advanced HCC. This study demonstrates that HUA reverses SOR resistance in HCC and exhibits synergistic effects with SOR by modulating NCOA4-mediated ferritinophagy, thereby influencing iron and lipid metabolic pathways associated with ferroptotic vulnerability. In SOR-resistant Huh7 cells and mouse xenograft models, HUA alone or combined with SOR disrupted iron homeostasis through ferritinophagy induction, promoted Fe reduction to Fe, enhanced ROS generation, induced lipid peroxidation, and concurrently reduced lipid droplet storage and triglyceride accumulation. Mechanistically, HUA upregulated NCOA4 and increased the LC3B-II/I ratio, leading to FTH1 degradation. Accumulated Fe drove robust ROS production via the Fenton reaction, exacerbated lipid peroxidation, upregulated ACSL4, and downregulated SCD1 and GPX4, collectively inducing ferroptosis, a form of regulated cell death specifically rescued by ferrostatin-1 or deferoxamine but not by Z-VAD-FMK or necrostatin-1, with minimal caspase activation. Furthermore, this cascade markedly downregulated PLIN2, resulting in energy depletion in Huh7 cells and tumor tissues, thereby impairing adaptive survival and ultimately reversing SOR resistance. Notably, NCOA4 silencing substantially attenuated HUA's efficacy in overcoming SOR resistance. These findings highlight the role of HUA in promoting NCOA4-dependent ferritinophagy and modulating iron and lipid metabolism to enhance ferroptotic sensitivity, providing a rationale for the clinical development of HUA + SOR combination therapy in HCC.
Stage-dependent association of Vitamin D receptor with macrophage polarization in allergic rhinitis.
Huang Y, Shi D, Zhang M … +2 more , He J, Peng S
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42235895 · Publisher ↗
BACKGROUND: Allergic rhinitis (AR) is driven by Th1/Th2 imbalance, with macrophages as key mediators. Vitamin D (VitD) deficiency is associated with AR; however, how VitD regulates macrophage-related molecules remains un...
BACKGROUND: Allergic rhinitis (AR) is driven by Th1/Th2 imbalance, with macrophages as key mediators. Vitamin D (VitD) deficiency is associated with AR; however, how VitD regulates macrophage-related molecules remains unclear. OBJECTIVE: This study investigated stage-specific effects of VitD receptor (VDR) signaling on macrophage-related molecules and immune responses in an ovalbumin (OVA)-induced AR rat model. METHODS: Beginning in the sensitization phase, rats received either the VDR agonist paricalcitol or the antagonist ZK168281. Outcomes were assessed during sensitization, re-challenge, and chronic maintenance phases, including nasal symptoms, nasal mucosal histopathology, serum OVA-specific IgE and M1/M2-like macrophage associated cytokines, spleen-derived cell transcriptomics, and nasal immunofluorescence for NOS2/ARG1 (M1/M2-like markers). RESULTS: Our findings demonstrate that VDR activation conferred maximal protection during the re-challenge phase, characterized by alleviated nasal symptoms, attenuated epithelial injury and inflammatory infiltration, and reduced OVA-specific IgE levels. Transcriptomic analysis revealed stage-dependent association of macrophage polarization: VDR signaling promoted the expression of M2-like-associated genes (e.g., Arg1, Cd163, and Mertk) during sensitization and chronic maintenance while suppressing M1-like inflammatory mediators and chemokines (e.g., Il6, Il1β, Cxcl9/10, and Ccl2) during re-challenge. These findings were corroborated at the protein level, with the serum cytokine analysis showing suppression of M1-like associated IL-6 and TNF-α, and nasal mucosal immunofluorescence confirming consistent and marked ARG1 expression upregulation. CONCLUSION: VDR signaling is associated with stage-dependent immunomodulation in AR, promoting M2-like molecules expression during sensitization and suppressing M1 like driven inflammation during re-challenge, thereby weakening effects in the chronic phase. These findings support a "chronotherapeutic" application of VitD in AR.
Co-eluting post-translational modification isoforms in collagen reveal fundamental challenge of LC-MS/MS site-specific analysis.
Nigam A, Basak T
Biochim Biophys Acta Proteins Proteom · 2026 Jun · PMID 42235871 · Publisher ↗
Collagen is a highly abundant extracellular matrix protein characterized by repetitive Gly-X-Y motifs and extensive post-translational modifications (PTMs), including hydroxylation of proline and lysine residues as well...
Collagen is a highly abundant extracellular matrix protein characterized by repetitive Gly-X-Y motifs and extensive post-translational modifications (PTMs), including hydroxylation of proline and lysine residues as well as O-glycosylation of hydroxylysine residues. This PTM density generates numerous peptide isoforms that challenge confident identification and quantification by LC-MS/MS. In this study, we have performed a systematic analysis of co-eluted, near-isobaric collagen peptides arising from site-specific PTM heterogeneity from the ECM of different mouse tissues. Using a publicly available healthy mouse tissue ECM proteomics dataset and a PTM-aware database search strategy, we demonstrate that near-isobaric collagen peptides frequently co-elute and co-fragment, producing chimeric spectra with high-confidence peptide-spectrum matches for multiple isoforms. Despite robust MS/MS evidence, overlapping retention times (RT) and identical m/z values prevent unambiguous localization of modification sites, necessitating exclusion from quantitative analyses. Our findings show that such co-elution reflects genuine biological heterogeneity rather than technical noise and highlight a critical gap between the complexity of collagen PTMs and current computational proteomics workflows, underscoring the need for advanced separation and PTM-aware analytical strategies.
Natural radiosensitizers in cancer therapy: Mechanisms, radioresistance modulation, and translational prospects.
Abdollahi A, Imani A, Rassouli FB
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42235835 · Publisher ↗
Cancer radiotherapy has made significant strides, yet the persistent challenge of tumor radioresistance continues to compromise therapeutic success. This obstacle stems from a multifaceted network of biological mechanism...
Cancer radiotherapy has made significant strides, yet the persistent challenge of tumor radioresistance continues to compromise therapeutic success. This obstacle stems from a multifaceted network of biological mechanisms, including enhanced DNA damage response, checkpoint dysregulation, hypoxia, metabolic reprogramming, and adaptations within the tumor microenvironment. The superior biocompatibility of phytochemicals positions them as promising candidates for combination approaches, and they have gained increasing attention as safer and mechanistically diverse radiosensitizers. Five major classes of phytochemicals, including coumarins, flavonoids, alkaloids, polyphenols, and terpenoids, are systematically reviewed. Promising radiosensitizing effects have been reported for coumarins, such as auraptene and osthole, as well as for flavonoids, including quercetin, luteolin, and apigenin. The repertoire of natural radiosensitizers is further expanded by alkaloids, such as piperlongumine and berberine, polyphenols, like curcumin and resveratrol, and terpenoids, such as thymoquinone. Despite encouraging preclinical findings, several consistent and critical limitations have been identified across the literature, including the absence of standardized efficacy metrics, heterogeneity in experimental designs, sparse in vivo validation, and unaddressed questions regarding normal cell selectivity. Consequently, clinical validation remains nascent, with only a few early-phase trials having investigated flavonoid-based formulations. By critically synthesizing current evidence and identifying translational gaps, this review provides a foundation for the future development of phytochemical radiosensitizers as viable adjuncts in multimodal cancer therapy.
A comprehensive review of microfluidic-based organ-on-chip technology in the application of preclinical drug discovery studies.
Shetty S, Kumar NAN, Kabekkodu SP … +1 more , Chakrabarty S
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42235834 · Publisher ↗
Microfluidic organ-on-chip (OoC) technologies have emerged as reliable platforms for the physiologically accurate simulation of human tumours by precisely modulating cellular, biochemical, and biomechanical parameters. T...
Microfluidic organ-on-chip (OoC) technologies have emerged as reliable platforms for the physiologically accurate simulation of human tumours by precisely modulating cellular, biochemical, and biomechanical parameters. This review critically examines recent advancements in organ-on-chip (OoC) systems for applications in precision oncology, immuno-oncology, preclinical drug discovery, therapeutic response assessment, and mechanistic studies of therapeutic resistance. Unlike traditional preclinical models, OoC systems integrate patient-derived tumour tissues, stromal and immunological components, and three-dimensional microenvironments to more accurately reflect tumour heterogeneity and therapeutic response. We further explored how these technologies enable the real-time evaluation of drug sensitivity, immunological interactions, hypoxia-driven adaptability, and stroma-mediated resistance, providing functional insights beyond genetic profiling. By incorporating recent developments in patient-derived models, immunooncology, mechanobiology, and clinically relevant drug response prediction, this review underscores the translational and mechanistic significance of OoC technologies, distinguishing it from previous reviews that primarily focused on microfabrication and device engineering. We also address contemporary challenges related to standardisation, regulatory validation, scalability, and reproducibility. Collectively, OoC technologies hold significant potential to advance precision medicine, enhance translational oncology, and reduce reliance on animal models in cancer research.
Corrigendum to "TAOK3 promotes ccRCC progression by phosphorylating ASAP2" [Biochim. Biophys. Acta. Mol. Basis. Dis. 2026 Jun; 1872 (5): 168210].
Zheng X, Cheng J, Zhang M … +6 more , Sun M, Huang Z, Han Y, Wu R, Li Y, Zhang C
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42230258 · Publisher ↗
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Engrailed, a target of the miR-92 family, attenuates Tau accumulation and associated memory deficits in Drosophila.
Nguyen MN, Ryu TH, Lee JS … +4 more , Hong SH, Yoon SE, Kim YJ, Yu K
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42229860 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated Tau protein. While...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated Tau protein. While microRNAs (miRNAs) have emerged as critical regulators of gene expression and potential biomarkers for AD, their role in Tau pathology remains incompletely understood. In this study, we investigated the role of the miR-92 family and its downstream targets in modulating Tau-induced neurodegeneration using the Drosophila model. Overexpression of miR-311, miR-312, and miR-313, members of the miR-92 family, exacerbated Tau-induced phenotypes. We identified deltex (dx) and engrailed (en) as miR-92 target genes with genetic screening with in silico target prediction. Overexpression of en or EN2, a human ortholog of en, reduced Tau protein levels in Drosophila and human neuroblastoma cells, respectively. Furthermore, overexpression of en attenuates Tau-associated memory deficits in Drosophila. These findings suggest that the engrailed gene is an evolutionarily conserved regulator of Tauopathy and highlight the utility of the Drosophila AD model for identifying genetic modulators with therapeutic potential in AD.
MEF2A/KMT2D/H3K4me3/LOX axis promotes osteoclast differentiation by increasing autophagic flux and participates in LPS-induced osteolysis.
Lu K, Han H, Li Z … +3 more , Gan C, Zhou S, Shi H
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42229859 · Publisher ↗
Overactivation of osteoclasts represents the core pathological mechanism driving bone destruction and pathological osteolysis, yet safe and effective targeted therapeutic strategies remain lacking in clinical settings. L...
Overactivation of osteoclasts represents the core pathological mechanism driving bone destruction and pathological osteolysis, yet safe and effective targeted therapeutic strategies remain lacking in clinical settings. Lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, has been linked to osteoclast differentiation, but its precise regulatory role and molecular basis remain poorly defined. This study aimed to explore the function of LOX in osteoclast differentiation and elucidate the underlying mechanisms. We observed that LOX expression gradually increased during osteoclastogenesis, accompanied by enhanced autophagic flux. Knockdown of LOX markedly suppressed osteoclast formation and autophagic activity, whereas overexpression of LOX exerted the opposite effects. Mechanistic studies revealed that combined treatment with si-LOX and the autophagy inhibitor 3-methyladenine further reduced the expression of key osteoclast-related proteins, while the autophagy activator rapamycin partially reversed these inhibitory effects. Epigenetic analysis showed that the methyltransferase KMT2D was upregulated during osteoclast differentiation, accompanied by significantly increased H3K4me3 modification at the LOX promoter. Manipulating KMT2D expression correspondingly altered H3K4me3 enrichment and LOX transcription. Moreover, KMT2D interacted with transcription factor MEF2A and was recruited to the LOX promoter, thereby mediating LOX transcriptional activation. In vivo, local injection of LV-shLOX lentivirus effectively attenuated LPS-induced mouse calvarial osteolysis. Collectively, our results demonstrate that LOX promotes osteoclast differentiation by enhancing autophagic flux, which is transcriptionally upregulated via the MEF2A/KMT2D/H3K4me3 axis. LOX may represent a promising therapeutic target for osteolytic bone disorders.
Mitochondria-mediated tumor drug resistance: From mechanism insights to therapeutic strategies.
Pi P, Yang L, Xie W … +2 more , Zhao J, Liang B
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42229770 · Publisher ↗
Drug resistance remains a major barrier to durable responses to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. Mitochondria, once viewed mainly as bioenergetic organelles, are now recognized as adaptive...
Drug resistance remains a major barrier to durable responses to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. Mitochondria, once viewed mainly as bioenergetic organelles, are now recognized as adaptive signaling hubs that shape tumor survival under therapeutic pressure. Here, we review how mitochondrial dynamics, metabolic plasticity, redox remodeling, programmed cell death regulation, epithelial-mesenchymal transition, and intercellular mitochondrial transfer collectively drive tumor drug resistance. We highlight that resistant cancer cells exploit mitochondrial flexibility to switch between glycolysis and oxidative phosphorylation, reinforce antioxidant defenses, suppress apoptosis, ferroptosis, and cuproptosis, and remodel the tumor microenvironment through metabolic and immune crosstalk. We further discuss emerging therapeutic strategies targeting mitochondrial vulnerabilities, including OXPHOS inhibition, fusion-fission modulation, redox intervention, BH3 mimetics, ferroptosis/cuproptosis induction, and mitochondria-directed delivery systems. Finally, we propose a mechanism-guided translational framework to advance mitochondria-targeted therapies toward biomarker-driven precision oncology. This integrated perspective may help move mitochondria-targeted therapy from a broad preclinical concept toward biomarker-guided precision strategies for overcoming tumor drug resistance.
Targeting the FABP4-PPARγ axis with IPA improves obesity-related glomerulopathy.
Li S, Qin Y, Zou J … +4 more , Xu C, Peng W, Zhou C, He C
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42229605 · Publisher ↗
Obesity-related glomerulopathy (ORG) is a significant renal complication associated with obesity, characterized by glomerular fibrosis and lipid accumulation. The underlying molecular mechanisms remain poorly understood,...
Obesity-related glomerulopathy (ORG) is a significant renal complication associated with obesity, characterized by glomerular fibrosis and lipid accumulation. The underlying molecular mechanisms remain poorly understood, necessitating the exploration of potential therapeutic targets. This study aimed to investigate the effects of indole-3-propionic acid (IPA) on the modulation of key proteins involved in ORG. Utilizing virtual screening, we identified fatty acid-binding protein 4 (FABP4) as a target protein for IPA. Our findings revealed that IPA did not alter the expression of FABP4, but it significantly increased protein abundance of peroxisome proliferator-activated receptor γ (PPARγ). Mechanistically, IPA competitively binds to FABP4, thereby disrupting the FABP4-PPARγ interaction. This reduction in binding led to decreased degradation of PPARγ, ultimately resulting in attenuated renal fibrosis and reduced lipid deposition in a PPARγ-dependent manner. These results suggest that IPA may serve as a potential therapeutic agent for the treatment of ORG by modulating the FABP4-PPARγ axis.
Cyclase-associated protein 1 facilitates actin-dependent mitochondrial fission in podocytes associated with diabetic nephropathy.
Ma H, Yao S, Wang Z … +5 more , Yu X, Li Z, Zhang R, Liang H, Jiao J
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42225185 · Publisher ↗
Aberrant mitochondrial dynamics in podocytes are closely associated with the progression of diabetic nephropathy (DN); however, the underlying mechanisms remain incompletely understood. Recent research has demonstrated t...
Aberrant mitochondrial dynamics in podocytes are closely associated with the progression of diabetic nephropathy (DN); however, the underlying mechanisms remain incompletely understood. Recent research has demonstrated that cyclase-associated protein 1 (CAP1), an actin-binding protein, mediates mitochondrial fission. Therefore, we aimed to explore the regulatory role and mechanisms of CAP1 in high glucose (HG)-induced mitochondrial dysfunction in podocytes. CAP1 knockout reduced the severity of glomerular injuries and curtailed mitochondrial fission in podocytes in streptozotocin (STZ)-induced DN models. Subsequently, we observed that HG levels induced the mitochondrial translocation of CAP1 in podocytes, and CAP1 inhibition mitigated excessive mitochondrial fission. Mechanistically, our findings demonstrate that CAP1 facilitates HG-induced mitochondrial fission in podocytes by modulating actin reorganization. Furthermore, we present evidence that CAP1 interacts with Cofilin1, and this interaction plays a role in enhancing HG-induced mitochondrial fission in podocytes. This study elucidates the critical role of CAP1 in facilitating HG-induced mitochondrial fission in podocytes by regulating actin dynamics. These findings offer novel insights for the prevention and treatment of DN.
Circular RNAs in virus-induced cancers: From mechanism to clinical implications.
Ahmed K, Jha S
Biochim Biophys Acta Rev Cancer · 2026 May · PMID 42218967 · Publisher ↗
Viruses, during their lifecycle, are continuously dependent on host machinery for their survival. Sometimes this dependency leads to uncontrolled cell proliferation in the host, accounting for 12% of virus-associated can...
Viruses, during their lifecycle, are continuously dependent on host machinery for their survival. Sometimes this dependency leads to uncontrolled cell proliferation in the host, accounting for 12% of virus-associated cancers. Since early times, viruses have been known to produce proteins and dysregulate host proteins, but what is new to the field is the addition of a circular regulatory RNA called "circRNA". circular RNAs, due to their structure-associated stability and specificity for various cancers, are key RNA molecules for researchers seeking to understand the complex outcomes of virus-associated cancers. circRNAs can serve as both therapeutic targets and diagnostic markers due to their unique back-spliced junctions formed by back-splicing of pre-mRNA and their presence in bodily fluids. Additionally, they can be potential candidate for vaccine development. This review provides a detailed overview of how viral and host circRNAs in seven oncogenic virus-associated cancers collectively reconstruct distinct host proteins, microRNAs, and mRNAs. It discusses the discovery, biogenesis, and function of circRNAs; their roles as therapeutic targets and diagnostic markers; and the emergence of new computational and Artificial Intelligence (AI)-driven circRNA modeling.
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