Acta biochimica et biophysica Sinica最新文献

Myocardial infarction (MI) is an acute cardiovascular condition with a poor prognosis, imposing substantial disease and economic burdens worldwide. The histone demethylase KDM5A is known to respond to oxygen levels; however, its role in MI remains unclear. Ferroptosis plays a decisive role in myocardial injury; however, whether it is regulated by KDM5A epigenetically remains unknown. Here, we establish an MI mouse model via left anterior descending coronary artery ligation and a hypoxic HL-1 cardiomyocyte model. Cardiac function, infarct size, and ferroptosis markers (Fe ^{2 +} and MDA) are assessed following KDM5A pharmacological inhibition or genetic manipulation. Epigenetic mechanisms are investigated using Cut&Tag analysis, qPCR, and western blot analysis. The results reveal that KDM5A promotes ferroptosis and aggravates cardiac injury. Inhibition of KDM5A significantly alleviates infarct damage. Cut&Tag analysis indicates that KDM5A binds to the Gdf15 promoter, thereby removing H3K4me3 and suppressing Gdf15 transcription. These changes result in the downregulation of glutathione peroxidase 4 (GPX4) and enhance ferroptosis. These findings suggest that KDM5A drives cardiomyocyte ferroptosis through the GDF15-GPX4 axis. This study identifies KDM5A as an epigenetic regulator of ferroptosis and a promising therapeutic target for MI.

The docetaxel-carboplatin (TCb) combination is a widely used neoadjuvant chemotherapy regimen, yet its clinical application is frequently accompanied by hepatotoxicity and drug-induced liver injury (DILI). However, the underlying molecular mechanisms remain incompletely understood. This study investigates the role of cGAS-STING-mediated autophagy in TCb-induced DILI. A TCb-induced DILI mouse model is established by intraperitoneal administration of docetaxel (10 mg/kg) and carboplatin (50 mg/kg) once weekly for two weeks, alongside an in vitro AML12 hepatocyte model (docetaxel 20 μM + carboplatin 100 μM). Liver injury, apoptosis, autophagy, and cGAS-STING signaling are evaluated using histopathological staining, biochemical assays, RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. TCb treatment induces significant liver injury, as evidenced by elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL), histopathological damage, and increased collagen deposition. TCb markedly promotes hepatocyte apoptosis, characterized by increased expression of Bcl-2 associated X protein (BAX) and decreased expression of Bcl-2. Concomitantly, TCb suppresses basal autophagy, as indicated by p62 accumulation, reduced Beclin-1 expression, decreased LC3-II/I ratio, and diminished autophagosome formation. Mechanistically, TCb robustly activates the cGAS-STING pathway, accompanied by enhanced phosphorylation of TBK1 and IRF3. Notably, pharmacological inhibition of STING with C-176 or siRNA-mediated STING knockdown restores autophagic flux and significantly attenuates TCb-induced apoptosis. Collectively, these findings suggest that sustained activation of the cGAS-STING pathway contributes to TCb-induced DILI by impairing autophagic homeostasis and promoting hepatocyte apoptosis. Targeting cGAS-STING-mediated autophagy represents a potential therapeutic strategy for preventing chemotherapy-associated hepatotoxicity.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of novel therapeutic targets. The transmembrane protein MAL2 has been implicated in various cancers, but its functional role and mechanistic underpinnings in HCC are not fully understood. To comprehensively understand its role in HCC, we analyze public single-cell RNA sequencing (scRNA-seq) data and find that MAL2 is significantly enriched in malignant HCC cells. In vitro, MAL2 is stably knocked down by shRNA in Hep-3B and HCC-LM3 cell lines, and functional experiments including colony formation, EdU, transwell, and wound healing assays demonstrate that MAL2 depletion markedly suppresses proliferation, invasion, and migration of HCC cell lines. In vivo, a subcutaneous tumor model using H22 cells reveals that MAL2 knockdown inhibits tumor growth, accompanied by reduced Ki-67 level and increased apoptosis. Further analysis via mass cytometry indicates that MAL2 downregulation reshapes the immune microenvironment, notably reducing CD4 ⁺ T cells, Tregs, CD8 ⁺ T cells, and exhaustion markers (PD-L1, PD1, and TIGIT) while increasing B cells and myeloid-derived suppressor cells (MDSCs). Mechanistically, ELISA and immunofluorescence staining validate that MAL2 knockdown impairs the secretion of CCL22, a chemokine known for recruiting Tregs, leading to reduced Treg recruitment and decreased production of the immunosuppressive cytokines IL-10 and TGF-β. In conclusion, MAL2 drives HCC progression by promoting tumor cell proliferation, invasion, and immunosuppression through CCL22-mediated Treg recruitment, positioning MAL2 as a promising therapeutic target to counteract tumor growth and remodel the immunosuppressive microenvironment in HCC.

Estrogen-associated signals regulating osteoclast apoptosis control osteoclast numbers. Enhancing anti-apoptotic activity during M-CSF and RANKL stimulation, which promotes osteoclast differentiation, increases the number of osteoclasts. Cell cycle and apoptosis regulator 2 (CCAR2) significantly modulates cancer cell survival and apoptosis by interacting with estrogen receptor α (ERα). Because CCAR2 regulates cell fate through ERα, we hypothesize that CCAR2 may inhibit the formation of bone-resorbing osteoclasts. We screen a public database of inbred mouse strain information to identify correlations between Ccar2 mRNA expression in bone and bone mineral density (BMD). We find that Ccar2 expression correlates positively with femoral and spine BMD. In addition, an increased abundance of osteoclasts is observed in aged mice, but the expression of CCAR2 in osteoclasts is lower in old mice than in young mice. To identify the role of CCAR2 in osteoclasts, we generate CCAR2-knockout (KO) RAW 264.7 cells using CRISPR-Cas9. The CCAR2-KO cells exhibit increased osteoclast numbers, reduced intracellular ROS levels, and decreased apoptosis during M-CSF- and RANKL-induced osteoclastogenesis. Mechanistically, CCAR2 binds to ERα, altering its nuclear translocation and increasing apoptotic transcriptional activity. These findings suggest that CCAR2 inhibits osteoclast numbers by increasing ERα-mediated apoptosis.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF), yet the underlying mechanisms remain poorly defined. Given that mitochondrial dysfunction represents a central feature of HFpEF pathophysiology, we investigate whether modulation of mitochondrial homeostasis contributes to the cardioprotective effects of dapagliflozin. Using a Dahl salt-sensitive rat model of HFpEF, we find that dapagliflozin markedly improves diastolic function and attenuates cardiac hypertrophy, fibrosis, and apoptosis. These beneficial effects are accompanied by significant restoration of mitochondrial structure and function. Consistently, in an in vitro HFpE model, dapagliflozin enhances mitochondrial respiratory capacity in cardiomyocytes, indicating a direct mitochondrial regulatory effect. Mechanistically, integrative transcriptomic and experimental analyses identify the SIRT1/PGC-1α/Mitofusin-2 (Mfn-2) signaling axis as a critical pathway suppressed in HFpEF but reactivated following dapagliflozin treatment. Activation of this pathway promotes mitochondrial biogenesis and improves mitochondrial dynamics, thereby preserving cardiomyocyte homeostasis. Collectively, our findings reveal that dapagliflozin exerts cardioprotective effects in HFpEF by restoring mitochondrial homeostasis through the SIRT1/PGC-1α/Mfn-2 axis, providing mechanistic insight into SGLT2i-mediated benefits and highlighting mitochondrial regulation as a potential therapeutic strategy for HFpEF.

E74-like ETS transcription factor 3 (ELF3) has been implicated in various tumorigenesis and inflammatory diseases. However, its expression profile and role in lung adenocarcinoma (LUAD) remain poorly defined. In the present study, through comprehensive clinical and experimental analyses, we aim to clarify the association between ELF3 overexpression in LUAD tissues and poor prognosis. Functional assays reveal that ELF3 knockdown inhibits the proliferation, migration, and invasion of LUAD cells, while ELF3 overexpression enhances these functions. Pathway enrichment analysis indicates that ELF3 influences the metabolic processes of LUAD. Mechanistically, ELF3 exerts oncogenic effects by regulating the transcription of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1). High-throughput screening reveals that dacinostat, by targeting the active site of the ELF3 protein, attenuates the glycolytic, proliferative, and metastatic abilities of LUAD cells. Additionally, ubiquitin-specific peptidase 18 (USP18) strengthens the stability of the ELF3 protein and influences the malignant biological behavior of LUAD through ELF3. In conclusion, the USP18/ELF3/HK2 and USP18/ELF3/GLUT1 axes play critical roles in glucose metabolism, proliferation, and metastasis of LUAD cells. Dacinostat inhibits the malignant progression of LUAD by targeting ELF3, providing strong evidence for developing novel therapeutic strategies targeting ELF3.

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent malignancy with limited therapeutic options. Ferroptosis is an iron-mediated type of programmed cell death, and it has surfaced as a viable oncology treatment approach. Curcumin (Cur) is a natural polyphenol that exhibits potent anti-tumor properties; however, the underlying molecular mechanisms regarding cell death modalities in HNSCC remain underexplored. The results of this study show that Cur is an effective ferroptosis inducer in HNSCC based on transcriptomic sequencing analysis. Cur treatment triggers hallmark ferroptosis characteristics that include iron accumulation, lipid peroxidation, radical oxygen species generation, and mitochondrial damage. These effects are all reversed by the ferroptosis inhibitor ferrostatin-1. Furthermore, we discover that Cur promotes the lysosomal degradation of ferritin heavy chain 1 (FTH1). Specifically, Cur enhances the interaction between the cargo receptor, nuclear receptor coactivator 4 (NCOA4), and FTH1, facilitating ferritinophagy. NCOA4 knockdown blocks FTH1 degradation and rescues HNSCC cells from Cur-induced ferroptosis. These results demonstrate that Cur triggers ferroptosis in HNSCC through NCOA4-mediated ferritinophagy. The results of this study highlight the NCOA4-FTH1 axis as a promising therapeutic target and support Cur as a potential candidate for HNSCC treatment.

Carbendazim (CBZ) and procymidone (PRO) are two fungicides widely used for decades. With excessive use, potential public health risks from their coresidues in vegetables and the environment have attracted increasing attention. Here, 6-week-old male SD rats are orally gavaged with 200 mg/kg CBZ, 200 mg/kg PRO, or 200 mg/kg CBZ + 200 mg/kg PRO (Mix group). At 1, 8 and 72 h postexposure, liver samples were collected and subjected to untargeted metabolomic analysis. Sparse partial least squares discriminant analysis (sPLS-DA) shows that all treatment groups exhibit significant separation from the Control group. Meanwhile, the Mix group is also significantly separated from the individual treatment groups. At 1 and 8 h postexposure, differentially abundant metabolites are predominantly enriched in fatty acyls according to HMDB classification, and the levels of 12-keto-eicosatetraenoic acid (12-KETE) are significantly elevated across treatment groups. 12-KETE acts as a PPARγ ligand and regulates PPARγ signaling pathways. The Mix-8 h group exhibits the largest number of differentially abundant metabolites. KEGG enrichment analysis identifies two uniquely enriched pathways with high impact (phenylalanine, tyrosine and tryptophan biosynthesis and linoleic acid metabolism). Within these pathways, linoleic acid, 13(S)-HPODE and L-tyrosine are significantly decreased only in the Mix-8 h group. Time-course analysis reveals diverse patterns of altered differentially abundant metabolites rather than a simple monotonic trend. Additionally, hepatic metabolite profiles remain separated among treatment groups after 72 h postexposure, although CBZ and PRO residues are hardly detected. Collectively, these results indicate that coexposure to CBZ and PRO amplifies hepatic metabolic disruption and produces mixture-specific toxic effects.

The widespread application of PARP inhibitors (PARPis) in epithelial ovarian cancer has led to the emergence of therapy resistance as a critical clinical challenge. To investigate the underlying mechanisms, we perform RNA sequencing of paired patient samples obtained before and after PARPi treatment, revealing a significant upregulation of glycolytic activity following therapy. Olaparib-resistant OVCAR8 and A2780 cells are established by exposure to increasing concentrations of Olaparib, and pharmacological inhibition or knockdown of GLUT1 restores Olaparib sensitivity, with synergistic effects confirmed in patient-derived organoids and xenograft models. Mechanistically, GLUT1 suppression reduces lactate accumulation, subsequently impairing tumor proliferation and DNA repair capacity through downregulation of the DNA repair protein MRE11. These findings establish lactate as a key mediator of PARPi resistance and propose targeting lactate metabolism as a promising combination strategy to improve PARPi efficacy in advanced ovarian cancer.

Capsular contracture, a common complication following breast implant surgery, is driven by fibroblast-to-myofibroblast transition and excessive collagen deposition. Although bacterial biofilm and TGF-β signaling are implicated, the molecular mechanisms linking infection to fibrosis remain unclear. Using in vitro fibroblast models and in vivo rat capsular contracture assays, we combine transcriptomics, protein interaction analysis, and targeted mutagenesis to identify Spata13 as a critical mediator of TGF-β/Smad signaling. Functional assays assess collagen synthesis (hydroxyproline content), fibroblast proliferation (CCK-8), and myofibroblast markers (α-SMA). A competitive peptide (PT637) is designed to disrupt Spata13-TGFβRI binding. Staphylococcus epidermidis biofilm synergizes with silicone implants to upregulate Spata13, activates TGF-β/Smad signaling, and promotes fibroblast activation. Spata13 binds to TGF-β receptor I (TGFβRI) via Ser637, and its knockdown suppresses α-SMA expression and collagen deposition. The TGFβRI inhibitor LY2157299 attenuates fibrosis in vivo. Strikingly, PT637 disrupts the Spata13-TGFβRI interaction and reduces both fibrosis markers and capsular thickness in biofilm-challenged rats. We define Spata13 as a novel regulator of infection-associated fibrosis and demonstrate that targeted disruption of Spata13-TGFβRI binding by PT637 offers a precision therapeutic strategy for capsular contracture.