Acta biochimica et biophysica Sinica最新文献

The orphan nuclear receptor NR2F1 has been shown to associate with a dormant tumor state in multiple tumor models. However, its dynamic regulation, particularly at the level of protein post-translational modification, remains largely unclear. In this study, we identify the deubiquitinase ubiquitin-specific peptidase 11 (USP11) as a potential regulator that controls the protein stability of NR2F1. USP11 directly interacts with NR2F1, and its overexpression increases NR2F1 protein level by suppressing NR2F1 protein turnover. Mechanistically, USP11 deubiquitinates NR2F1 at K70 and K369 to protect it from proteasomal degradation. Consistent with these findings, USP11 and NR2F1 expression levels are positively correlated across multiple tumor types. Notably, elevated expression of either USP11 or NR2F1 predicts a better prognosis in kidney renal clear cell carcinoma, indicating their potential clinical significance. Together, these findings reveal a post-translational regulatory mechanism of NR2F1 and suggest that targeting USP11 may provide a potential strategy for modulating tumor dormancy.

Abnormal cardiac lipid metabolism is a major contributor to cardiovascular disease (CVD). The nuclear receptor Rev-erb-α is recognized as a regulator of lipid metabolism; however, its role in cardiomyocyte lipotoxicity remains undefined. This study aims to investigate the functional role of Rev-erb-α in palmitic acid (PA)-induced lipid accumulation and peroxidation in cardiomyocytes. H9c2 cardiomyocytes are treated with the canonical Rev-erb agonists SR9009 and GSK4112 in combination with PA. Intracellular lipid droplet accumulation is quantified using Oil Red O, Nile red, and BODIPY 493/503 staining. Cytoplasmic and mitochondrial reactive oxygen species (ROS) levels are measured using 2',7'-DCFDA, dihydroethidium, and Mito-SOX probes, respectively, while DNA damage is assessed by quantifying the markers 53BP1 and γ-H2AX. Additionally, siRNA-mediated knockdown and adenovirus-mediated overexpression of Rev-erb-α are employed to validate its role in H9c2 and/or neonatal rat ventricular cardiomyocytes. PA treatment downregulates Rev-erb-α protein expression. Surprisingly, both SR9009 and GSK4112 exacerbate lipid droplet production and ROS production while activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway, independent of Rev-erb-α. However, direct adenovirus-mediated overexpression of Rev-erb-α significantly attenuates lipid droplet formation and mitochondrial ROS, which is reversed by the Nrf2 inhibitor brusatol. Mechanistically, Rev-erb-α functions as a transcriptional activator of Nrf2. Our results demonstrate a direct protective role for Rev-erb-α against lipotoxic stress and crucially reveal that its commonly used agonists have confounding, off-target pro-oxidant effects. These findings have critical implications for developing Rev-erb-α-targeted therapies for CVDs.

Relapsed/refractory multiple myeloma (RRMM) is characterized by high mortality rates and limited survival, with real-world studies reporting substantial mortality and median survival of only a few years after relapse. Immunomodulatory drugs (IMiDs) are a cornerstone of first-line multiple myeloma (MM) therapy, yet resistance remains a major clinical challenge. Resistance to pomalidomide has been attributed to multiple mechanisms, including CRBN downregulation and activation of pro-survival signaling pathways such as NF-κB; however, the contribution of epigenetic regulators, particularly the STAT3EZH-STAT3 axis, remains insufficiently explored. In this study, our analysis of public datasets identifies significant upregulation of enhancer of zeste homolog 2 (EZH2) in RRMM patients together with an association between EZH2 expression and poor prognosis. Using two established pomalidomide-resistant MM models, we confirm elevated EZH2 expression in pomalidomide-resistant MM cell lines, and demonstrate targeting EZH2 via small interfering RNA or the selective inhibitor GSK343 elicits potent anti-myeloma effects in pomalidomide-resistant MM models. Notably, EZH2 knockdown increases the sensitivity of RRMM cells to pomalidomide, providing a rationale for combining EZH2 inhibition with pomalidomide therapy. Consistent with this observation, GSK343 synergizes with pomalidomide to suppress MM progression both in vitro and in vivo. To better understand the mechanisms involved, we conduct RNA sequencing and investigate potential mediators of EZH2. We find that EZH2 contributes to pomalidomide resistance through stabilizing STAT3 protein, thereby supporting myeloma cell survival under therapeutic stress. In conclusion, EZH2 inhibition can enhance the therapeutic efficacy of pomalidomide against RRMM, indicating that EZH2 offers a promising target for overcoming drug resistance in MM.

The development of homologous food and medicine products often involves a trade-off between maintaining a pure and natural profile and optimizing flavor. The relatively monotonous taste of Dendrobium officinale has substantially limited its market expansion. Within D. officinale, phloretin and its glycosides are present, yet the natural sweetener trilobatin (phloretin-4'- O-glucoside) is absent. Different glycosylation positions often confer distinct taste properties on specific metabolites. Following melatonin treatment, there is a predominant enrichment of flavonoid pathways in D. officinale, accompanied by a notable decrease in phloretin levels, suggesting a possible upregulation of its glycosides. Subsequently, we annotate 135 uridine diphosphate-dependent glycosyltransferases (UGTs) in D. officinale and identify three phloretin UGTs, among which the enzymatic product trilobatin has been scarcely detected. Through functional modifications of these UGTs using AlphaFold and molecular docking, we have achieved a functional shift in DoUGT885 from solely producing phlorizin to trilobatin via mutation of the M2 fragment. The alteration of fragment M5 enables DoUGT019, which originally possessed multisite glycosylation functionality for phloretin, to primarily produce trilobatin as its main enzymatic product. The discovery of these key amino acid residues crucial for trilobatin formation serves as candidate insertion or substitution sequence fragments for gene editing, significantly advancing the creation of sweet D. officinale germplasm.

Traditional photothermal antibacterial therapy is limited by a narrow therapeutic window. Here, myricetin-functionalized Prussian blue analog nanoparticles (M@HPBA) are developed as a multimodal platform for methicillin-resistant Staphylococcus aureus (MRSA) infection and wound repair. Doping with cobalt, zinc, and copper enhances photothermal conversion and enzyme-mimetic activities. Under near-infrared irradiation, localized heating induces bacterial damage and triggers the controlled release of metal ions and myricetin. Released myricetin scavenges excess reactive oxygen species, alleviating oxidative stress and inflammation to promote healing. In vitro, M@HPBA with irradiation achieves high antibacterial efficiency against MRSA. In a murine wound infection model, this strategy markedly reduces bacterial burden and accelerates tissue regeneration, with a wound closure rate significantly higher than controls. Transcriptomic analysis reveals that M@HPBA regulates inflammatory and antioxidant pathways in MRSA-infected wounds, enhancing susceptibility to photothermal and ROS/metal ion killing. M@HPBA demonstrates broad-spectrum antibacterial activity and favorable biosafety. These findings establish a synergistic strategy integrating photothermal therapy, nanozyme catalysis, ion release, and antioxidant intervention, providing a translatable paradigm for precision antimicrobial therapy and infected wound management.

Pannexin 1 (PANX1), a member of the gap junction protein family, is ubiquitously expressed across various tissues and plays a key role in ATP release and signal transduction. In this study, we investigate Panx1 expression in cardiac fibroblasts under pathological conditions, specifically focusing on heart failure. Transcriptomic analysis reveals that Panx1 expression is upregulated in mouse hearts after transverse aortic constriction (TAC) surgery. Single-cell sequencing data from TAC mice indicate that Panx1 is predominantly expressed in fibroblasts, and its expression is significantly elevated in TAC mice. The upregulation of the PANX1 protein in fibroblasts following TAC is further corroborated by immunofluorescence staining and western blot analysis. Similarly, single-cell sequencing data from human heart failure patients are consistent with those from TAC mice, showing high PANX1 expression in fibroblasts. Pathway enrichment analysis of fibroblasts with differential Panx1 expression reveals that the JAK/STAT signaling pathway is commonly enriched in both species. In vitro knockdown and overexpression of the Panx1 gene are used to demonstrate its effect on the fibroblast phenotype. In vivo injection of a PANX1 blocker provides evidence for the role of Panx1 in alleviating cardiac fibrosis. The PANX1 channel is expressed in cardiac fibroblasts and is upregulated after TAC. Bioinformatics analysis suggests that this process is associated with the JAK/STAT signaling pathway. The Panx1 gene regulates phenotypic changes in fibroblasts and activates the downstream JAK/STAT signaling pathway via the ATP-purinergic receptor.

Phenazine biosynthesis-like domain-containing protein (PBLD) has been proven to be a critical regulator of tumor suppression and antiviral innate immunity; however, its role in pyroptosis remains unexplored. Our current investigation shows that PBLD promotes pyroptosis in bovine parainfluenza virus 3 (BPIV3)- or herpes simplex virus type 1 (HSV-1)-triggered HeLa cells, along with BPIV3- or bovine ephemeral fever virus (BEFV)-infected BHK-21 cells, as manifested by increased hallmark features of pyroptosis, including cell swelling, plasma membrane disintegration, elevated lactate dehydrogenase (LDH) release, and reduced cell survival. Further studies reveal that PBLD facilitates virus-induced pyroptosis mediated by GSDME N-terminal cleavage but independent of GSDMD cleavage. Using caspase-specific inhibitors and knockout cell lines, we identify Caspase-3, but not Caspase-8, as essential for virus-induced GSDME-dependent pyroptosis. Mechanistically, PBLD enhances Caspase-3 activation by upregulating PUMA mRNA levels via the NF-κB signaling pathway. Furthermore, silencing of NF-κB abolishes PBLD-induced PUMA upregulation and Caspase-3 and GSDME cleavage. In summary, these findings reveal that PBLD potentiates virus-triggered pyroptosis through the NF-κB/PUMA/Caspase-3/GSDME signaling pathway. This investigation provides unprecedented understanding of the molecular mechanisms by which PBLD regulates cell death and highlights its promise as a pharmacological target for viral infections and inflammatory diseases.

Hyperglycemia is a poor prognostic factor in critically ill septic patients with diabetes. Acute lung injury (ALI) resulting from hyperglycemia combined with sepsis remains an urgent clinical challenge. However, the mechanisms by which hyperglycemia contributes to sepsis-associated ALI remain unclear. In this study, we investigate the molecular mechanisms through which hyperglycemia accelerates ALI and mortality in sepsis using in vivo and in vitro models. High NPM3 expression not only mediates H3K18la levels but also promotes its binding to the ACSL1 promoter. Elevated ACSL1 expression and abnormal subcellular organelle localization disrupt lipid metabolism in macrophages, ultimately leading to ferroptosis. Our findings indicate that hyperglycemia enhances ferroptosis via the NPM3-H3K18la-ACSL1 axis in macrophages during sepsis-associated ALI. Targeted inhibition of this axis effectively suppresses hyperglycemia-induced ferroptosis in macrophages and reduces ALI and mortality in septic mice. Thus, targeting the NPM3-H3K18la-ACSL1 axis represents a promising therapeutic strategy for hyperglycemic/diabetic patients with sepsis-associated ALI.