Apoptosis最新文献

Background

Pyroptosis contributes significantly to neuronal death following ischemic stroke. This study investigated whether lactylation of heat shock protein family A member 8 (HSPA8) modulates neuronal pyroptosis after ischemic/reperfusion injury.

Research design and methods

Both in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models and in vivo transient middle cerebral artery occlusion (tMCAO) mouse models were established to assess the functional significance of HSPA8 lactylation at lysine 524 (K524).

Results

HSPA8 expression and lactylation increased following ischemic/reperfusion injury both in vitro and in vivo. K524 was the predominant lactylation site, regulated by p300 acetyltransferase and histone deacetylases. The lactylation-mimetic K524Q mutant significantly reduced pyroptosis markers (NLRP3, GSDMD, cleaved caspase-1) and pyroptotic cell death compared to wild-type or K524R mutant. In tMCAO mice, neuronal expression of HSPA8-K524Q reduced infarct volume and suppressed pyroptosis more effectively than K524R. Mechanistically, HSPA8 lactylation at K524 enhanced its interaction with the E3 ubiquitin ligases PARK2 and ARIH2, promoting NLRP3 ubiquitination and degradation.

Conclusions

HSPA8 lactylation at K524 is a critical regulator of neuronal pyroptosis and ischemic brain injury. This modification facilitates E3 ligase-mediated NLRP3 degradation and suppression of inflammasome activation. Targeting protein lactylation pathways may offer a promising therapeutic strategy for neuroprotection in ischemic stroke.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents for various cancers, including cholangiocarcinoma (CCA) and colorectal cancer (CRC). However, its therapeutic efficiency has remained unsatisfactory. A better understanding of the molecular mechanisms underlying 5-FU responsiveness is therefore crucial for developing more effective treatment strategies and improving patient survival. Mixed lineage kinase domain-like protein (MLKL), a key regulator of necroptosis, has been implicated in cancer progression and therapeutic response. However, the exact roles of MLKL in modulating chemotherapy response, particularly 5-FU, has also remained unknown. Through a comprehensive bioinformatics analysis, we identified a significant association between high MLKL expression and poor therapeutic outcomes in CCA and CRC patients treated with 5-FU. Moreover, higher MLKL expression was detected in CRC patients who were clinically unresponsive to 5-FU-based treatments compared to responders, suggesting a crucial role of MLKL in mediating 5-FU response. Of particular interest, MLKL depletion sensitized CRC cells to 5-FU and enhanced its tumor-suppressive effects in a xenograft mouse model by promoting apoptosis. We propose that MLKL suppression potentiate TNF-α/TNFR-I-mediated apoptotic signaling, potentially by prolonging TNFR-I retention within the early endosome and delaying its degradation upon 5-FU treatment. Notably, silencing of TNFR-I attenuated 5-FU-induced cell death in MLKL-knockdown cells. These findings provide novel insights into previously unrecognized roles of MLKL in modulating 5-FU responsiveness and highlight MLKL as a potential predictive and therapeutic target to improve 5-FU efficacy in precision cancer therapy.

Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer’s disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.

In recent years, the application of estrogen in skin health and disease prevention has garnered significant attention, and it is now widely involved in the intervention and study of various skin conditions. Experimental evidence shows that estrogen has profound effects on the structure and function of the skin, including the synthesis of collagen and elastin, regulation of skin pigmentation, and control of sebum secretion. This review systematically summarizes the multifaceted effects of estrogen on skin health and diseases, with a focus on the mechanisms by which different types of estrogen influence skin aging, pigmentation, and other related issues. Additionally, we explore how estrogen exerts its effects on the skin through various signaling pathways, such as estrogen receptor-mediated signaling, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) pathways. Through a comprehensive analysis of the existing studies, this review aims to provide a deeper understanding of the complex interactions between estrogen and the skin, offering a comprehensive perspective on estrogen’s role in skin physiology and pathology.

Graphical abstract

A Ovarian production and receptor-mediated systemic effects; B Modulation of cutaneous pathologies; C Nuclear (nER) and membrane (mER) receptor pathways; D Novel skin-lightening agents derived from plant estrogens; E Natural, phyto-, synthetic, and xenoestrogens)

Traditional chemotherapeutic agents are indispensable in cancer treatment. However, their therapeutic efficacy is frequently constrained by associated toxicities and adverse effects. Among these adverse effects, cardiotoxicity has emerged as a major clinical concern due to the increasing incidence. Emerging evidence suggests that oxidative stress, programmed cell death pathways, oxidative stress, and inflammatory cascades predominantly mediate the pathogenesis of cardiotoxicity induced by chemotherapeutic agents. Current strategies for monitoring and prevention rely on potential biomarkers, including markers of myocardial injury (e.g., troponins and natriuretic peptides), inflammatory mediators (e.g., myeloperoxidase, interleukin-6, C-reactive protein, and tumor necrosis factor-alpha), and exosomal contents (e.g., microRNAs, proteins, and metabolites). Clinical trials and case reports have demonstrated that patients with chemotherapy-induced cardiotoxicity may benefit from therapeutic interventions such as angiotensin-converting enzyme inhibitors, dexrazoxane, and β-blockers. However, limitations associated with these potential biomarkers and therapeutic agents warrant further discussion because of the lack of solid evidence from large-scale, prospective clinical studies. In summary, further research is imperative to enhance the understanding, monitoring, and therapeutic management of cardiotoxicity associated with traditional chemotherapeutic agents.

This study aimed to investigate the roles of ANXA7 and its upstream regulator RNF168 in Crohn’s disease (CD) progression, focusing on their interaction with inflammation and intestinal mucosal barrier disruption. Colon tissues from CD patients, including inflamed and uninflamed tissues, were analyzed to assess ANXA7 expression. The biological functions of ANXA7 were studied in vitro using LPS/ATP-stimulated NCM460 cells, employing ANXA7 knockdown and overexpression experiments. Protein–protein interactions were examined using co-immunoprecipitation (Co-IP) and mass spectrometry. The regulatory role of RNF168 in ANXA7 degradation was explored through Co-IP and ubiquitination assays. The effects of RNF168 and ANXA7 on autophagy and NLRP3 inflammasome-induced pyroptosis were assessed. In vivo experiments were conducted using IL-10 knockout (KO) mice, RNF168^{flox/flox; Villin−Cre} mice with TNBS-induced colitis, and organoids to investigate the therapeutic potential of RNF168 and ANXA7 manipulation. ANXA7 expression was significantly reduced in inflamed tissues and correlated with CD-related inflammatory markers. RNF168 promoted the ubiquitination and degradation of ANXA7, thereby suppressing autophagy and inducing NLRP3 inflammasome-mediated pyroptosis. The in vitro and in vivo biological functions of sh-RNF168 were rescued by sh-ANXA7. ELK1 was identified as a key transcription factor regulating RNF168 expression, linking transcriptional regulation with inflammation and disease progression. Our findings suggest a mechanistic model where ELK1 upregulates RNF168, leading to ANXA7 degradation, suppression of autophagy, and enhanced pyroptosis, thereby promoting CD progression and intestinal barrier disruption. Targeting the RNF168-ANXA7 axis offers a potential therapeutic strategy for CD.

S-palmitoylation, a reversible lipid post-translational modification, plays a dynamically regulatory role in cell death signaling pathways by modulating protein-membrane affinity, subcellular localization, and functional interactions. Emerging evidence has linked dysregulated S-palmitoylation to various pathologies including cancer and neurodegenerative disorders. Recently, several advances highlight its novel involvement in ferroptosis, an iron-dependent programmed cell death mechanism characterized with lipid peroxidation and iron accumulation. However, the precise regulatory impact of S-palmitoylation on ferroptosis remains to be fully elucidated. Notably, certain key regulators of ferroptosis undergo degradation through autophagy pathways, indicating an intricate crosstalk between ferroptosis and autophagy. Herein, the current review summarized the molecular mechanisms and physiological functions of ferroptosis and S-palmitoylation, with a particular focus on the pivotal role of palmitoylated ferroptosis-related regulators. Importantly, the interaction between autophagy and ferroptosis, especially the S-palmitoylated proteins that modulate both processes were discussed as well. This review provides a new perspective for the accurate regulation of ferroptosis by modulating S-palmitoylation, thus may improve the overall prognosis through optimizing the treatment regimens or via enhancing the efficacy of existing therapies.

Colorectal cancer (CRC) ranks among the most prevalent and lethal malignancies globally, with Cetuximab (CTx) resistance being a significant hurdle in its treatment. To uncover the underlying mechanisms, this study recruited 27 metastatic CRC patients undergoing CTx-based therapy and categorized them into responder and non-responder groups. In addition to measuring succinate levels in serum and tumor tissues and evaluating M2 macrophage infiltration in patients, a series of in vitro and in vivo experiments were conducted. In vitro, HT29 and Caco2 cells were treated with CTx and succinate under different conditions, including monoculture and co-culture with macrophages. The results indicated that succinate enhanced CRC cells’ resistance to CTx specifically in the presence of macrophages by promoting M2 macrophage polarization. This effect was found to be mediated by succinate receptor 1 (SUCNR1), as demonstrated by experiments involving SUCNR1 knockdown. In vivo, the addition of succinate promoted tumor growth and weakened the inhibitory effect of CTx through macrophages. Further exploration revealed that succinate-induced polarized tumor-associated macrophages secreted IL-6, which played a crucial role in conferring CTx resistance. Overall, this study uncovers that tumor-secreted succinate confers CTx resistance in CRC by activating SUCNR1, thereby driving M2 macrophage polarization. These findings offer novel insights into the mechanisms of CRC resistance and identify potential therapeutic targets within the tumor microenvironment, which could potentially lead to the development of more effective treatment strategies for CRC patients.

Extracellular matrix (ECM) detachment is crucial for metastasis in cancer cells. During tumorigenesis, a programmed cell death occurs to clear off the ECM detached cancer cells in the circulatory system; this phenomenon is referred to as anoikis. Metastatic cancer cells can evade anoikis by regulating mechanisms such as cell adhesion, cell growth, oxidative stress, cancer stemness, hypoxia and metabolic reprogramming. Studies have shown that RNA modifications regulate multiple cancer mechanisms; however, the role of RNA modifications in anoikis resistant is not established yet. Therefore, in this study, we assessed the role of N6-methyladenosine (m6A) modification of mRNAs in anoikis resistant conditions. First, we cultured cancer cells in low adhesive plates for six (6) days followed by quantitative real-time PCR (qRT-PCR) of major m6A regulators and quantification of the global m6A levels in detached versus attached cancer cells. We also assessed cell proliferation in detached cancer cells using STM2457, a potent and specific METTL3 inhibitor. Our results showed a significant (p < 0.05) increase in METTL3 expression and activity in anoikis resistant cancer cells. Furthermore, we observed an elevation in global m6A levels on mRNAs. Treatment of anoikis resistant cancer cells with STM2457 caused reduction in spheroid size, induction of apoptosis, and cell cycle arrest which were correlated with a decrease in global m6A levels. Conclusively, our findings reveal that METTL3-dependent m6A methylation sustains the survival and proliferation of anoikis-resistant cancer cells, highlighting an epitranscriptomic mechanism underlying metastatic fitness.

Copper is essential for cellular homeostasis and can induce cuproptosis, a novel form of cell death. However, its effect on cancer progression, specifically through the regulation of epithelial-mesenchymal transition (EMT)—a primary driver of metastasis and treatment resistance in human cancers—remains unclear. This study assessed the dual role of copper in colorectal cancer cells, focusing on the polo-like kinase 1-forkhead box O3a-beta catenin (PLK1-FOXO3a-β-catenin) signaling pathway. Treatment with CuCl₂ (hereby referred to as Cu) alone facilitated EMT in SW480 and LoVo cells by upregulating PLK1 and downregulating FOXO3a that enhanced β-catenin activity without inducing cell death. In contrast, co-treatment with Cu and copper ionophore elesclomol (Cu-ES) triggered cuproptosis, a unique copper-dependent form of cell death, accompanied by mitochondrial dysfunction, dihydrolipoamide S-acetyltransferase aggregation, and ATP depletion. Specifically, Cu-ES treatment suppressed EMT by reducing PLK1 and activating FOXO3a that suppressed β-catenin-mediated transcription. Additionally, while Cu treatment alone had minimal effect on FOXO3a nuclear localization, Cu-ES treatment significantly enhanced FOXO3a nuclear translocation and its interaction with β-catenin, resulting in EMT gene repression. The PLK1 inhibitor BI-2536 recapitulated the effects of Cu-ES and exhibited synergistic activity when combined with Cu-ES, enhancing both cell death and EMT suppression. These findings highlight a novel regulatory mechanism of EMT through copper signaling and support copper-based combination therapies as a promising approach to simultaneously inhibit tumor growth and metastasis in colorectal cancer.