Apoptosis最新文献

Pyroptosis is a new type of programmed cell death that plays an important role in neuronal injury after subarachnoid hemorrhage (SAH). The effect of natural compounds in SAH has attracted much attention. Hsperetin has been found to have neuroprotective effects in ischemic stroke, but its role in SAH has not been studied. An in vivo model of SAH in male C57BL/6 mice is constructed by the endovascular perforation method, and the heme intervention HT22 cells simulate the in vitro SAH model. After administration of hesperetin, SAH grade, brain water content (BWC), modified garcia score, neurobehavior tests, cerebral blood flow, transmission electron microscope, western blot, and immunofluorescence staining were conducted. Our study found that hesperetin significantly alleviated neurobehavioral deficits, improved cerebral blood flow, and reduced the expression of NLRP3, GSDMD-N, Caspase-1, ASC, IL-18, which were also demonstrated in vitro. Mechanistically, hesperetin notably promoted mitophagy by regulating DHCR24 and BACE1, thereby inhibiting neuronal pyroptosis. This effect was eliminated by U18666A and 3-MA administration. Our findings demonstrated that hesperetin alleviated neuronal pyroptosis by promoting mitophagy via DHCR24/BACE1 to provide neuroprotective effects on EBI. These results suggest that hesperetin has the potential to be a therapeutic target for SAH.

Chemotherapy failure caused by adriamycin (ADM) and imatinib (IM) resistance remains a critical challenge in the treatment of chronic myeloid leukemia (CML). In this study, a novel compound 4, 4’-(selenophene-2, 5-diyl)bis(3-fluorophenol) (Se-1) with estrogen receptor regulation and selenium anticancer activity was applied to reverse drug resistance of CML. Se-1 exhibited superior inhibitory activity against resistant K562/ADM cells compared to sensitive K562 cells. The growth of K562/ADM in xenograft mouse was suppressed by Se-1 treatment. The anti-leukemia mechanism of Se-1 was tested by western-blot, flow cytometry, molecular docking and fluorescence imaging. The apoptosis rate was increasing after Se-1 treatment, meanwhile proteins of Cleaved PARP and Cleaved Caspase3 were up-regulated and Bcl-2 was down-regulated. In addition, the autophagy was activated through increasing of autophagy vesicles and proteins of LC3-II and P62, and inactivating of mTOR protein. Moreover, estrogen receptor α (ERα), ERK and P38 were activated, the proteins of PI3K and AKT1 were decreased. Overall, Se-1 exerted anti-CML effects through multi-mechanism interaction, which was expected to advance the research in reversing ADM and IM resistance of chronic myeloid leukemia.

Triple-negative breast cancer (TNBC) is characterized by a highly immunosuppressive tumor microenvironment (TME), which contributes to its poor clinical outcomes. Tumor-associated macrophages (TAMs) constitute a major cellular component of the TME, and the dominance of immunosuppressive M2 phenotype, rather than the pro-inflammatory M1 phenotype, plays a pivotal role in maintaining immune evasion. Reprogramming TAMs from M2 to M1 phenotype represents a promising therapeutic strategy for reversing immunosuppression in TME. In the current study, our findings demonstrated that JQ1, a bromodomain and extra-terminal motif (BET) protein inhibitor, effectively promotes macrophage polarization toward the M1 phenotype both in vitro and in vivo. Furthermore, JQ1 enhances the cytotoxic and phagocytic capacity of TAMs. Mechanistic studies revealed that JQ1 inhibits PPARγ signaling, thereby shifting TAMs toward the M1 phenotype and subsequently promoting T cell-mediated antitumor immunity. Importantly, treatment with JQ1 in combination with anti-CD47 antibody synergistically suppressed 4T1 tumor growth. Our findings uncovered a novel immunomodulatory function of JQ1 in reprogramming TAMs polarization within the TNBC TME and provided a compelling rationale for targeting BET proteins in cancer immunotherapy.

N6-methyladenosine (m6A) RNA modification plays a pivotal role in gynaecological cancers by regulating tumor initiation, progression, and therapeutic resistance. m6A RNA modification include writers (METTL3/14, RBM15, ZC3H13, WTAP), which catalyze methylation; erasers (ALKBH5, FTO), which remove methyl groups; and readers (YTHDC1, YTHDF1/2/3, IGF2BP1/2/3, HNRNPC/G, HNRNPA2BP1), which interpret m6A marks to regulate the RNA fate. These regulators alter basic RNA metabolism, such as splicing, mRNA stability, translation, and degradation. In gynaecological cancers, both oncogenic and tumor suppressive signaling pathways are also altered by these regulators. Due to their diagnostic, prognostic and predictive value, m6A regulators have emerged as promising biomarkers in gynaecological cancers in recent years. This review highlights the role of m6A regulators and critically evaluates their biomarker and clinical potential in gynaecological cancers.

Circular RNAs (circRNAs) have been identified as important mediators of tumorigenesis and tumor progression. This study focuses on circAGFG1, a circRNA with elevated N6-methyladenosine (m6A) modification, and its role in triple-negative breast cancer (TNBC). Fluorescence in situ hybridization and qPCR analyses revealed that circAGFG1 is significantly upregulated in TNBC tissues and in the TNBC cell line MDA-MB-231. Functional characterization using loss-of-function and gain-of-function strategies in two TNBC cell lines demonstrated that circAGFG1 promotes oncogenic phenotypes. Specifically, knockdown in MDA-MB-231 cells suppressed proliferation, invasion, migration, and G1/S phase transition, while its overexpression in MDA-MB-468 cells promoted these processes. Mechanistically, western blotting and PCR analyses indicated that circAGFG1 modulates the expression of epithelial-mesenchymal transition markers N-cadherin and α-SMA. Furthermore, we identified that YTHDF3, an m6A reader protein upregulated in TNBC, upregulates circAGFG1 expression by enhancing its transcript stability. Finally, dual-luciferase reporter assays confirmed that circAGFG1 acts as a sponge for miR-1299, thereby potentially modulating the miR-1299 signaling pathway. Collectively, our findings delineate the critical role of the circAGFG1 in promoting TNBC progression, highlighting its potential as a novel therapeutic target.

Ferroptosis, a distinct form of regulated cell death, has attracted significant attention due to its critical role at the intersection of cellular metabolism, redox biology, and various human diseases. Macrophages play a key role in maintaining systemic iron balance, and their specific polarization states influence the regulation of ferroptotic processes. However, the therapeutic potential of ferroptosis in cancer is frequently limited by tumor-associated macrophages (TAMs), representing a significant challenge in applying immunotherapy to hematologic malignancies. Notably, inducing ferroptosis in macrophages themselves also holds therapeutic promise. This review synthesizes recent advances in macrophage ferroptosis research to clarify its role in disease pathogenesis. Importantly, we highlight the translational potential of the ferroptosis-TAM axis, suggesting that biomarker-guided modulation of this pathway, via novel nanocarriers or combination treatments, represents a paradigm-shifting strategy to overcome drug resistance and restore antitumor immunity in hematologic malignancies.

Background

The upregulated expression of sterol regulatory element-binding protein 2 (SREBP2) has been observed in multiple types of malignant cancers. Ferroptosis is a form of cell death that is iron-dependent and driven by the accumulation of lipid peroxides. It has recently garnered considerable attention in Colorectal cancer (CRC) research. This study aims to investigate the role of SREBP2 in CRC ferroptosis resistance and the underlying molecular mechanisms.

Methods

SREBP2 expression was assessed in CRC. Functional assays were conducted in HT29 and RKO cells following SREBP2 knockdown or treatment with Betulin, the SREBP2 inhibitor. RNA-seq was used to screen the potential downstream targets of SREBP2. Mechanistically, ferroptosis-related markers and rescue assays revealed the relation between SREBP2 and CRC ferroptosis resistance mediated by GPX4 expression regulation. Furthermore, ChIP and luciferase assays were used to confirm the upstream that regulates SREBP2 expression. Finally, subcutaneous tumorigenesis model was employed to evaluate the therapeutic potential of targeting SREBP2 in CRC.

Results

The upregulated SREBP2 expression in CRC drives the proliferation, migration, and invasion of CRC cells. Mechanistically, SREBP2 directly increases GPX4 transcription, thereby reducing the sensitivity of CRC to ferroptosis and facilitating CRC progression. Additionally, β-catenin was identified as an upstream regulator of SREBP2. Inhibition of SREBP2 sensitizes CRC cells to ferroptosis and suppresses tumor growth.

Conclusion

SREBP2 enhances ferroptosis resistance in CRC by upregulating GPX4, thereby contributing to tumor progression. Our findings highlight SREBP2 as a potential therapeutic target and provide a rationale for the development of SREBP2-targeted strategies in colorectal cancer.

Hepatocellular carcinoma (HCC) remains the most common primary liver cancer, with a high incidence and mortality rate. Remarkable progress has been made in cancer treatment in recent years; however, most patients with HCC still receive limited benefits from current treatment options. Therefore, there is an urgent need to explore novel and effective therapeutic strategies. Here, a novel combination therapy consisting of the calcineurin inhibitor cyclosporine A (CsA) and the flavone-naphthalimide-polyamine derivative 6c was identified. The combination of CsA and 6c inhibited cell viability and colony formation and induced GSDME-dependent pyroptosis. Mechanistically, RNA sequencing revealed that CsA and 6c synergistically activated the RIG-I-like receptor (RLR) signaling pathway. Moreover, the combination of CsA and 6c promoted RIG-I and MDA5 expression, TBK1 and IRF3 phosphorylation, and downstream target gene expression. RIG-I deletion attenuated the combination treatment-induced inhibition of cell growth, pyroptosis, and expression of IFN-stimulated genes (ISGs). Furthermore, combination treatment induced the downregulation of LDHA expression, leading to increased reactive oxygen species (ROS) generation. LDHA overexpression and ROS removal reversed the inhibitory effect of the combination treatment on HCC. Finally, combination of CsA and 6c suppressed tumor growth and pulmonary metastasis in vivo. Overall, our study suggests a novel synergistic treatment combination with a comprehensive mechanistic exploration, demonstrating that it is a promising strategy for HCC treatment via targeting RIG-I-like receptor signaling.

Trastuzumab (TRZ), a monoclonal antibody targeting the ErbB2 protein, significantly improves the prognosis of patients with ErbB2-positive breast or gastric cancer; however, its cardiotoxicity substantially limits its clinical applicability in certain patient populations. TRZ-induced cardiotoxicity (TIC) primarily arises from ErbB2 signaling blockade, compromising cardiomyocyte repair mechanisms and functional integrity. This inhibition further compromises the cellular antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and triggering a cascade of downstream events, including apoptosis, inflammatory responses, ferroptosis, autophagy dysfunction, and pyroptosis. Based on the aforementioned mechanisms, researchers have conducted in-depth investigations into the molecular pathways involved in TIC. To date, decades of research have identified several keys signaling pathways implicated in TIC, including PI3K/Akt, MAPK, STATs, AMPK, mTOR, MDM2/p53, NLRP3, and NF-κB. Furthermore, a number of potential therapeutic agents targeting key molecules in TIC have been explored. However, these findings have not yet been summarized. Therefore, this review aims to comprehensively consolidate existing knowledge on TIC, elucidate its regulatory mechanisms, and provide insights for developing novel cardioprotective strategies.