Acta biochimica et biophysica Sinica最新文献

Cardiometabolic syndrome (CMS), a combination of central obesity, insulin resistance, dyslipidemia, and hypertension, accounts for a significant portion of the global incidence of type 2 diabetes and cardiovascular disease. Traditionally, hormonal and hemodynamic dysregulation have been considered the primary causes of CMS. However, increasing evidence shows that metabolic reprogramming, which involves long-lasting, tissue-specific changes in cellular metabolism, is a common cause of the initiation and progression of CMS. This review examines the systemic metabolic alterations, the molecular pathways facilitating these modifications, and the transformative impact of multiomics platforms on the discovery of novel biomarkers and therapeutic targets. We also discuss drugs that can help restore metabolic flexibility and stop disease progression.

The liver is a crucial site for fructose uptake and metabolism, a function intricately linked to fructose-associated pathologies. This study examines the role of hepatic ketohexokinase (KHK) in metabolic syndrome induced solely by high-fructose intake. Liver-specific Khk-deficient mice are generated and fed with a 20% fructose solution for 3 months, after which the features of metabolic syndrome are examined. Compared with fructose-fed floxed controls, fructose-fed liver-specific Khk-deficient mice present alleviated liver injury and hepatic steatosis, along with lower triglyceride levels in the plasma and liver, plasma aspartate transaminase and alanine transaminase levels, and mRNA levels of genes related to triglyceride and fatty acid synthesis. Liver-specific Khk deficiency also leads to lower uric acid levels in the plasma and urine, as well as xanthine oxidase activity and Glut9 mRNA levels in the liver and kidneys of fructose-fed mice. Although intestinal villus length and epithelial barrier integrity remain unaffected, the deletion of liver Khk significantly reduces fructose-stimulated KHK, Glut2, Glut5, and aldolase B expression in the intestine and kidneys, suggesting inhibited fructose absorption and metabolism in these tissues. In the adipose tissue, fructose-induced increases in adipocyte size and tumor necrosis factor-α and interleukin-6 mRNA levels are blocked by liver-specific Khk deficiency, indicating improved remodeling of adipose tissue and reduced inflammation in adipocytes. Overall, liver-specific Khk deletion is sufficient to protect against metabolic syndrome induced by excessive fructose intake. Our findings underscore the critical role of liver KHK-mediated fructose metabolism in driving the physiological and pathological consequences associated with fructose consumption along the intestinal-liver-kidney axis.

The newly discovered midnolin-proteasome pathway is a unique ubiquitin-independent mechanism for degrading nuclear proteins, which is crucial for maintaining cellular protein homeostasis. The Catch domain of midnolin is essential for substrate recognition and binding, yet the underlying mechanism for its broad substrate specificity remains elusive. Transcription factor IRF4, essential for the functions of B and T cells, is a substrate of midnolin. This study presents comprehensive biochemical and structural analyses of the human midnolin Catch domain in complexes with both wild-type and mutant IRF4 peptides. The crystal structure of the Catch-IRF4 complex reveals that the Catch domain creates a substrate-binding groove at the interface of the Catch1 and Catch2 subdomains, recognizing and binding to the 215-QVTGTFYAC-223 sequence motif of IRF4. The binding motif of IRF4 forms a β-strand that is embedded into the substrate-binding groove, resulting in an antiparallel five-stranded β-sheet. The interactions between the IRF4 peptide and the Catch domain are predominantly hydrophobic and exhibit high spatial complementarity. Additionally, the biochemical, modeling and structural data indicate that the V2 and A8 positions of the IRF4 sequence motif can be substituted with other hydrophobic or small polar residues (G/A/V/L/I/M/P/F/Y/C/S/T), but not with large polar and charged residues (D/N/E/Q/H/K/R). The G4 position can be replaced by Ser, while the F6 position can be substituted with Tyr. These results suggest that the Catch domain can recognize and bind to a variety of substrates containing the sequence motif x[G/A/V/L/I/M/P/F/Y/C/S/T]x[G/S]x[F/Y]x[G/A/V/L/I/M/P/F/Y/C/S/T]x or briefly the G/SxF/Y motif (where x represents polar residues) located in an unstructured or loop region on the protein surface, and the hydrophobic interactions and spatial complementarity between the binding motifs of substrates and the Catch domain govern the substrate specificity. Collectively, these findings elucidate the molecular basis for midnolin's broad substrate specificity.

Lethal prostate cancer is marked by tumor heterogeneity and resistance to androgen receptor signaling inhibitors (ARSIs). In this study we identify glycolysis as a driver of disease progression and therapy resistance. Using single-sample gene set enrichment analysis (ssGSEA) on the SU2C cohort, we demonstrate that elevated glycolysis activity is associated with poor progression-free and overall survival. The glycolysis-based prognostic score (GLY score) is derived from the HALLMARK_GLYCOLYSIS gene set which includes CLN6, SDHC, B4GALT2, RPE, NANP, and KIF20A, via LASSO-Cox regression. The GLY score effectively stratifies risk in the SU2C and WDCT cohorts, with higher scores predicting worse outcomes and increased SYNE1 mutation frequency. Pan-cancer analysis across TCGA datasets confirm its prognostic value. In vitro, enzalutamide-resistant prostate cancer cell lines exhibit heightened glycolysis, and 2-DG inhibition reverses this effect, restoring drug sensitivity. CLN6 knockdown reduces glycolytic activity and cell proliferation. The GLY score offers robust prognostic value, and CLN6 represents a promising therapeutic target for precision medicine in lethal prostate cancer.

Sepsis causes high mortality and resource strain, with neutrophil-derived reactive oxygen species (ROS) contributing to excessive inflammation. The secretory protein FAM19A4 modulates ROS release, but its role in sepsis is unclear. In this study, we find elevated FAM19A4 levels in septic patients and cecal ligation and puncture (CLP) mice, which correlate with increased mortality. Fam19a4 ^{-/ -} mice subjected to CLP show significantly improved survival and attenuated multiorgan injury without impaired peritoneal bacterial clearance or altered circulating neutrophil counts. FAM19A4 deficiency reduces the cell counts of neutrophils (Ly6G ⁺) and macrophages (F4/80 ⁺) in the lungs and liver, diminishes systemic ROS production tracked by bioluminescence, and decreases neutrophil extracellular trap (NET) formation in serum and lung tissue. In vitro, FAM19A4 enhances neutrophil phagocytosis and ROS generation but does not affect lipopolysaccharide-induced chemotaxis. Mechanistically, FAM19A4 drives neutrophil ROS release specifically through p38 MAPK signaling activation, as revealed by bulk RNA sequencing, western blot analysis, and treatment with p38 inhibitor SB203580. These results indicate that FAM19A4 is upregulated during sepsis and exacerbates outcomes by enhancing neutrophil ROS production via p38 MAPK, representing a promising therapeutic target for this condition.

Midnolin (MIDN) is a newly recognized master regulator that drives ubiquitin-independent proteasomal degradation, yet the mechanisms governing its own turnover remain enigmatic. Here, we demonstrate that MIDN is ubiquitinated and identify RNF126 as the cognate E3 ligase. RNF126 physically associates with MIDN and catalyzes its ubiquitination, and mass spectrometry mapping reveals that this process occurs primarily at non-canonical cysteine, serine, and threonine residues (C230, C236, S237, T239, and S241) rather than at lysine residues. This non-classical ubiquitination targets MIDN for 26S-proteasomal degradation. In vivo dissection of the RNF126-MIDN axis shows that it governs EGR1 abundance and, consequently, the tumor-suppressor proteins PTEN and p53, thereby restraining the progression of testicular germ-cell tumors (TGCTs). Our findings reveal an unappreciated layer of MIDN regulation and identify the RNF126-MIDN ubiquitination cascade as a potential therapeutic vulnerability in TGCTs and related malignancies.

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy characterized by a high relapse rate and a low survival rate. Although chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) have improved the prognosis for AML patients, the overall survival rate remains suboptimal. MLN4924 is a neddylation inhibitor and is considered a promising treatment approach for AML. However, the exact molecular mechanism remains elusive and requires further investigation. This study aims to investigate the molecular mechanisms of MLN4924 and novel molecular pathways in AML. RNA sequencing (RNA-seq) reveals that the transcription factor (TF) EGR1 serves as a core regulator of MLN4924 and is upregulated by MLN4924 in AML. Mechanistic studies demonstrate that MLN4924 induces apoptosis by generating reactive oxygen species (ROS) and facilitates the nuclear translocation of EGR1. This translocated EGR1 interacts with the promoter region of BTG2, promoting its transcription and inhibiting the progression of AML. Notably, the ROS generated by MLN4924 influences the expression of both EGR1 and BTG2 and establishes a positive feedback loop between EGR1 and ROS. In vivo, we confirm that MLN4924 reduces the leukemic burden in AML cell-derived xenograft models by increasing the expression of both EGR1 and BTG2. In conclusion, these findings suggest that MLN4924 exerts an anti-tumor effect on AML by inducing apoptosis through the ROS-EGR1-BTG2 signaling axis. Our research provides a novel theoretical basis for the clinical potential of MLN4924 in improving the treatment of AML patients, offers novel strategies for AML treatment, and thereby advances the implementation of precision medicine.

Ischemic stroke, a severe neurological disorder with a multifactorial pathogenesis, presents significant therapeutic challenges. Calycosin, a natural flavonoid, has diverse biological activities, including antioxidant, anti-inflammatory, and antitumor effects. In this study we investigate the protective effects of calycosin against blood-brain barrier (BBB) damage following cerebral ischemia-reperfusion injury (CIRI) and explore the underlying mechanisms. We employ middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation (OGD) in bEnd.3 brain microvascular endothelial cells to assess neurological function, BBB integrity, the expression of pyroptosis-related proteins, inflammatory mediator release, endothelial barrier permeability, and cell viability. The results reveal that calycosin significantly ameliorates CIRI-induced BBB damage, as evidenced by improved neurological scores, reduced brain water content, and decreased infarct volume. Calycosin suppresses NLRP3-mediated pyroptosis by downregulating HMGB1, NLRP3, caspase 1, GSDMD, N-GSDMD, and IL-18 expression while reducing the secretion of HMGB1, IL-1β, and IL-18. Additionally, calycosin enhances BBB integrity by decreasing MMP9 and AQP-4 expression and upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-5). In OGD-treated bEnd.3 cells, calycosin inhibits NLRP3-mediated pyroptosis, reduces inflammatory mediator release, and improves cell viability and barrier function. Notably, molecular docking and molecular dynamics simulations demonstrate that calycosin stably binds to NLRP3 with high affinity, supporting its potential as an NLRP3 inhibitor. These findings indicate that calycosin protects against CIRI-induced BBB damage by inhibiting NLRP3-mediated pyroptosis and modulating tight junction protein expression, indicating that calycosin is a potential therapeutic option for ischemic stroke.

Smurf1 is a member of the Nedd4 family of E3 ubiquitin ligases. Numerous lines of evidence indicate that the membrane localization of Smurf1 is essential for its activity. However, the underlying mechanisms that regulate the membrane localization of Smurf1 remain unclear. Type I phosphatidylinositol phosphate kinase (PIPKI) is a phosphatidylinositol kinase that generates phosphatidylinositol 4,5-bisphosphate (PIP2), which is located in the plasma membrane and regulates cellular processes, including ion channel activity and cell migration. In this study, we show that PIP2 and PIPKI regulate the membrane translocation of Smurf1. Importantly, the recruitment of Smurf1 to the cell membrane through the association of its C2 domain with PIPKI-produced PIP2 is essential for Smurf1-mediated E3 ligase activity and cell migration. Therefore, we identify a PIPKI-PIP2-Smurf1 signaling axis that regulates cell migration.