Background: Ischemia-reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Macrophage-mediated pyroptosis cascade plays a crucial effect in liver I/R injury. The attribution of pyroptosis in macrophage reprogramming and hepatic microenvironment during liver I/R remain unclear. Here, we identify AXL as a hepatic macrophage-enriched gene that regulates pyroptosis in I/R injury.
Methods: We collected liver grafts to test the relationship between phosphorylated AXL (p-AXL) and degree of hepatic injury. We isolated primary mouse hepatocytes and macrophages for hypoxia/reoxygenation (H/R) treatment and coculture, and used macrophage depletion mice to reveal the unique function of AXL in hepatic macrophages. Mice were treated with activators and inhibitors of AXL, NLRP3, and XBP1, and subjected to liver I/R to determine the mechanism underlying AXL-mediated modulation of the hepatic microenvironment.
Results: We found that AXL inhibition and NLRP3-induced pyroptosis was strongly associated with the degree of liver I/R injury. Further analysis revealed that AXL activation in macrophages suppressed hepatic I/R-induced pyroptosis. AXL activation with Gas6, a high-affinity ligand for AXL, significantly attenuated liver I/R injury and improved the hepatic microenvironment. Mechanistically, AXL activation impeded the IRE1-XBP1s axis to suppress NLRP3 inflammasome activation, which promoted hepatic macrophages to an alternative-like polarization, thereby enhancing the hepatic immune environment to attenuate liver I/R injury.
Conclusions: This study not only elucidates how AXL reprograms macrophages but also suggests a therapeutic target for mitigating liver I/R injury.
Epitranscriptomic modifications, as a dynamic and reversible system of chemical modifications, have emerged as a key regulatory hub for programmed cell death (PCD) by finely modulating the RNA metabolic network. During the pathological progression of liver diseases, aberrant alterations in epitranscriptomic modifications can disrupt the dynamic equilibrium of PCD signaling pathways, leading to excessive cell death or abnormal survival of hepatocytes, thereby driving the development of metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, alcohol-associated liver disease (ALD), hepatic fibrosis, and hepatocellular carcinoma (HCC). A thorough investigation into the molecular mechanisms of epitranscriptomic modifications in PCD pathways and their roles in liver diseases not only aids in elucidating the pathogenesis of liver disorders but also holds the potential to provide new biomarkers and therapeutic targets for the diagnosis, prognosis, and treatment of liver diseases. This review systematically summarizes the molecular mechanisms of epitranscriptomic modifications, delves into the complex regulatory networks between epitranscriptomic modifications and PCD, elaborates on their roles in liver diseases, and provides a comprehensive overview of current drugs targeting epitranscriptomic modifications. These insights offer new treatment ideas for liver diseases and new directions for precision medicine research.
Background: MMP14 protein has been recognized to promote tumor metastasis through protease activity, yet drugs targeting the protein fail to improve survival rates, suggesting the presence of non-protein regulatory mechanisms. This study aims to explore the roles and mechanisms by which MMP14 RNA facilitates colorectal cancer (CRC) metastasis.
Methods: Transwell assays and animal experiments utilizing loss-of-function and gain-of-function approaches were employed to assess the roles of MMP14 RNA in facilitating CRC metastasis. A combination of immunoprecipitation assays, scRNA-seq analysis, and western blotting was conducted to elucidate the underlying mechanisms by which MMP14 RNA promoted CRC metastasis.
Results: Our study revealed that MMP14 RNA was highly expressed in CRC tissues and correlated with poor prognosis. The overexpression of MMP14 RNA facilitated metastasis both in vitro and in vivo. Mechanistically, MMP14 RNA interacted with the distal promoter of STARD13 and bound to the N-terminal of SIRT3, facilitating its recruitment to the promoter region. This cascade of events reduced H3K27cr levels at the STARD13 promoter, thereby inhibiting STARD13 transcription and ultimately promoting CRC metastasis. Furthermore, we proved that silencing MMP14 RNA had a more significant inhibitory effect on tumor metastasis compared with inhibiting the MMP14 protein.
Conclusions: The study elucidated an lncRNA-like mechanism by which MMP14 RNA facilitated CRC metastasis via RNA-directed chromatin remodeling.
Catecholamines, canonically associated with the sympathetic nerves and the adrenal medulla, are also produced by neuroparacrine cells within the heart. Despite their putative importance, the precise functions of these neuroparacrine cells in the heart are not well understood and their clinical implications remain to be defined. In this review, we first explore the historical context and recent advances in research on intrinsic cardiac adrenergic (ICA) cells, focusing on their unique characteristics, distributions, and progenitor-like potential during cardiac development. We then examine their contributions to both physiological and pathological cardiac states. We further discuss a recently identified population of catecholaminergic cardiomyocytes; we discuss their involvement in cardiac development, maturation, and their potential interaction with sympathetic innervation during development. By reviewing these findings, we provide new insights into the endogenous production of catecholamines within the heart and its relevance to cardiac development, physiology and disease, and its potential clinical implications.
Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia due to impaired insulin production, action, or both. The Pancreas and Liver play central roles in glucose regulation, and their dysfunction is critical to the onset and progression of specific types of diabetes, including type 2 diabetes and certain forms of monogenic diabetes. While these organs have distinct physiological roles, they originate from the foregut endoderm and share key developmental regulators and signaling pathways. This review explores the overlapping transcription factors and genes that are essential for both pancreatic and hepatic development and function. These dual-role genes not only govern early organogenesis but are also implicated in diabetes pathogenesis, underscoring their significance in metabolic homeostasis. We highlight how interorgan signaling, particularly between hepatokines and pancreatic islet cells, contributes to the maintenance or disruption of glucose metabolism. Furthermore, we discuss the clinical implications of these shared pathways, emphasizing how insights from developmental biology can inform precision diagnostics and therapeutic strategies for diabetes. Finally, we consider how emerging tools, such as pluripotent stem cell-based disease models and gene editing and multi-omics approaches, are transforming our understanding of gene function and disease progression. By bridging the developmental and metabolic landscapes of the pancreas and liver, this review provides a comprehensive framework for uncovering novel regulators of diabetes and paves the way toward targeted, personalized treatment strategies.
Background: The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk.
Methods: To investigate the role of RSL3 during ferroptosis, we treated several cancer cells of different histological types with varying doses of RSL3 to induce apoptosis. The regulatory proteins of PARP1 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The N6-methyladenosine (m6A) modification level of PARP1 was determined by m6A RNA immunoprecipitation (MeRIP)-qPCR analysis. Additionally, an RNA immunoprecipitation (RIP)-qPCR assay was performed to identify the target protein of the m6A site of PARP1. Furthermore, we established a mouse xenograft model of PARP inhibitor (PARPi)-resistant cells to analyze the effect of RSL3 on PARPi-resistant tumor growth.
Results: RSL3 triggers two parallel apoptotic pathways via increasing reactive oxygen species (ROS) production during ferroptosis: (1) caspase-dependent PARP1 cleavage and (2) DNA damage-dependent apoptosis resulting from reduced full-length PARP1. The latter occurs through inhibition of METTL3-mediated m6A modification and subsequent suppression of PARP1 translation. Moreover, we found that RSL3 retains pro-apoptotic functions in PARPi-resistant cells and effectively inhibits PARPi-resistant xenograft tumor growth in vivo.
Conclusions: RSL3 orchestrates ferroptosis-apoptosis crosstalk via PARP1, demonstrating therapeutic potential against tumorigenesis, particularly in PARPi-resistant malignancies.
Immune-resistant pancreatic islets hold great promise for advancing diabetes cell therapy. Two key approaches, hypoimmunogenic pluripotent stem cells (PSCs) and hypoimmunogenic cadaveric islets, aim to overcome immune rejection in islet transplantation. Human PSCs provide a versatile source of insulin-producing cells, but immune rejection remains a major barrier. Recent advances in gene-editing technologies have enabled the modification of PSCs and cadaveric islets to reduce their immunogenicity. These cells can be engineered to express human leukocyte antigen (HLA)-negative profiles, while overexpressing immunoregulatory factors such as CD47, PD-L1, and HLA-G to evade T cell and natural killer (NK) cell immune-mediated responses. These modifications aim to generate "off-the-shelf" islet cell therapies compatible with a wide range of patients, potentially eliminating the need for immunosuppressants. However, ensuring long-term safety and functionality remains a challenge. Potential risks such as immune escape, viral infections, and tumorigenicity must be carefully addressed through additional safety measures. This review explores different approaches for generating hypoimmunogenic islets, recent advances in overcoming immune rejection, and key hurdles that need to be addressed for widespread clinical use for patients with diabetes. It also compares the potential benefits and limitations of hypoimmunogenic cadaveric islets versus hPSC-derived islets, providing insights into their future clinical applications.
Most of the canonical Arg-Gly-Asp (RGD)-containing integrin ligands are extracellular matrix proteins, such as fibronectin, vitronectin and fibrinogen, which regulate cell-ECM adhesion processes. However, during the last years, several reports have demonstrated the existence of non-canonical RGD-containing integrin ligands that are cell surface transmembrane proteins. At variance with the canonical extracellular matrix integrin ligands, the RGD-containing cell surface integrin ligands are involved in cell-cell adhesion processes and function as "integrin counter-receptors". We propose in this review grouping these transmembrane proteins, which include endoglin, cadherin-5, cadherin-6, cadherin-17, ADAM15, and L1CAM, under the newly coined acronym RGD-ICRs (RGD-containing Integrin Counter-Receptors). We present and discuss the structure of RGD-ICRs, their RGD-based interactions with integrins, the specific signaling pathways triggered in different cell types, as well as their pathophysiological involvement. It can be postulated that RGD-ICRs constitute an emerging group of non-canonical RGD-based integrin counter-receptors. In spite of being encoded by different and independent genes and involved in different pathophysiological processes, all of them appear to have undergone a strong evolutionary convergence in order to acquire the same functional capacity to bind integrins via the RGD motif. Importantly, these RGD-ICRs are also emerging as novel biomarkers and therapeutic targets, with promising clinical potential in a wide array of pathologies.
Triple-negative breast cancer (TNBC) is a particularly aggressive and therapeutically challenging subtype of breast cancer, defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This absence of actionable molecular targets contributes to its resistance to conventional treatments. This review provides an overview of the mechanistic functions, interrelated processes, and therapeutic implications of several programmed cell death (PCD) pathways-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-in the context of TNBC pathogenesis and treatment. A conceptual framework is proposed for leveraging these interconnected cell death pathways as a basis for novel targeted interventions. Given the complex interplay among various PCD forms characterized by shared features such as inflammation, mitochondrial dysfunction, and overlapping molecular mediators, this integrated network offers promising opportunities for combinatorial therapeutic strategies. Modulation of one cell death pathway may influence others, potentially amplifying therapeutic efficacy. Furthermore, these PCD pathways are highly relevant to immunotherapy outcomes, offering a foundation for synergistic treatment modalities. This review provides an in-depth analysis of the crosstalk between immune-based therapies and PCD, along with a comprehensive discussion of derived therapeutic approaches. However, tumor diversity, resistance mechanisms, and discrepancies between preclinical models and human physiology pose major challenges in applying these findings clinically. The overarching goal is to present innovative insights and strategies to enhance the clinical management of TNBC and ultimately improve patient outcomes.
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