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Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.

Background Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague. Aim of review This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate. Key scientific concepts of review This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.

Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as a critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers of lactate: L- and D-lactate. Recent studies have shown that disruptions in these two lactate stereoisomers have distinct effects on health and disease. L-lactate is central to glycolysis and energy transfer through the Cori cycle but also acts as the dominant lactylation isomer induced by glycolysis, influencing metabolism and cell survival. Although less studied, D-lactate is linked to metabolic disorders and plays a role in mitochondrial dysfunction and oxidative stress. This review focuses on both L- and D-lactate and examines their biosynthesis, transport, and expanding roles in physiological and pathological processes, particularly their functions in cancer, immune regulation, inflammation, neurodegeneration and other diseases. Finally, we assess the therapeutic prospects of targeting lactate metabolism, highlighting emerging strategies for intervention in clinical settings. Our review synthesizes the current understanding of L- and D-lactate, offering insights into their potential as targets for therapeutic innovation.

In recent 10 years, ferroptosis has become a hot research direction in the scientific research community as a new way of cell death. Iron toxicity accumulation and lipotoxicity are unique features. Several studies have found that ferroptosis is involved in the regulation of the hepatic microenvironment and various hepatic metabolisms, thereby mediating the progression of related liver diseases. For example, NRF2 and FSP1, as important regulatory proteins of ferroptosis, are involved in the development of liver tumors and liver failure. In this manuscript, we present the mechanisms involved in ferroptosis, the concern of ferroptosis with the liver microenvironment and the progression of ferroptosis in various liver diseases. In addition, we summarize recent clinical advances in targeted ferroptosis therapy for related diseases. We expect that this manuscript can provide a new perspective for clinical treatment of related diseases.

Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participates in mitochondrial bioenergetics through interaction with its partner coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) and involvement in mitochondrial protein import. These dual roles place AIF between pro-survival and pro-death cell fate decisions. In this review, we first describe the structure and the dual functions of AIF, highlighting its structure-function relationships. We then report previously identified AIFM1 mutations and their clinical phenotypes. Finally, we discuss the relevance of AIF in cancer and the potential of targeting this protein for the treatment of cancer.

Trained immunity serves as a de facto memory for innate immune responses, resulting in long-term functional reprogramming of innate immune cells. It enhances resistance to pathogens and augments immunosurveillance under physiological conditions. Given that innate immune cells typically have a short lifespan and do not divide, persistent innate immune memory may be mediated by epigenetic and metabolic changes in long-lived hematopoietic stem cells (HSCs) in the bone marrow. HSCs fine-tune their state and fate in various training conditions, thereby generating functionally adapted progeny cells that orchestrate innate immune plasticity. Notably, both beneficial and maladaptive trained immunity processes can comprehensively influence HSC state and fate, leading to divergent hematopoiesis and immune outcomes. However, the underlying mechanisms are still not fully understood. In this review, we summarize recent advances regarding HSC state and fate in the context of trained immunity. By elucidating the stem cell-intrinsic and extrinsic regulatory network, we aim to refine current models of innate immune memory and provide actionable insights for developing targeted therapies against infectious diseases and chronic inflammation. Furthermore, we propose a conceptual framework for engineering precision-trained immunity through HSC-targeted interventions.

Endothelial-mesenchymal transition (EndMT) is defined as an important process of cellular differentiation by which endothelial cells (ECs) are prone to lose their characteristics and transform into mesenchymal cells. During EndMT, reduced expression of endothelial adhesion molecules disrupts intercellular adhesion, triggering cytoskeletal reorganization and mesenchymal transition. Numerous studies have proved that EndMT is a multifaceted biological event driven primarily by cytokines such as TGF-β, TNF-α, and IL-1β, alongside signaling pathways like WNT, Smad, MEK-ERK, and Notch. Nevertheless, the exact roles of EndMT in complicated diseases have not been comprehensively reviewed. In this review, we summarize the predominant molecular regulatory mechanisms and signaling pathways that contribute to the development of EndMT, as well as highlight the contributions of a series of imperative non-coding RNAs in curbing the initiation of EndMT. Furthermore, we discuss the significant impact of EndMT on worsening vasculature-related diseases, including cancer, cardiovascular diseases, atherosclerosis, pulmonary vascular diseases, diabetes-associated fibrotic conditions, and cerebral cavernous malformation, providing the implications that targeting EndMT holds promise as a therapeutic strategy to mitigate disease progression.

Protein glycosylation, the most ubiquitous and diverse type of post-translational modification in eukaryotic cells, proteins are input into endoplasmic reticulum and Golgi apparatus for sorting and modification with intricate quality control, are then output for diverse functional glycoproteins that are utilized by cells to precisely regulate various biological processes. In order to maintain the precise spatial structure of glycoprotein, misfolded and unfolded glycoproteins are recognized, segregated and degraded to ensure the fidelity of protein folding and maturation. This review enumerates the role of five immune-related glycoproteins and reveals the relevance of glycosylation to their antigen presentation, immune effector function, immune recognition, receptor binding and activation, and cell adhesion and migration. With the knowledgement of glycoproteins in immune responses and etiologies, we propose several relevant therapeutic strategies on targeting glycosylation process for immunotherapy.

This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation–contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a “quasi-synaptic” mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.

Background Angiogenesis and osteogenesis are closely interrelated. The interaction between endothelial and bone-forming cells, such as osteoblasts, is crucial for normal bone development and repair. Juxtacrine and paracrine mechanisms play key roles in cell differentiation towards the osteogenic direction, assuming the direct effect of endothelium on osteogenic differentiation. However, the mechanisms of this interplay have yet to be thoroughly studied. Methods Isolated endothelial cells (EC) from human umbilical vein and human osteoblasts (OB) from the epiphysis of the femur or tibia were cultured in direct and indirect (separated by membrane) contact in vitro under the osteogenic differentiation conditions. Osteogenic differentiation was verified by RT-PCR, and alizarin red staining. Shotgun proteomics and RNA-sequencing were used to compare both EC and OB under different co-culture conditions to assess the mechanisms of EC-OB interplay. To verify the role of Notch signaling, experiments with Notch modulation in EC were performed by EC lentiviral transduction with further co-cultivation with OB. Additionally, the effect of Notch modulation in EC was assessed by RNA-sequencing. Results EC have opposite effects on osteogenic differentiation depending on the co-culture conditions with OB. In direct contact, EC enhance osteogenic differentiation, but in indirect cultures, EC suppress it. Our proteotranscriptomic analysis revealed that the osteosuppressive effect is related to the action of paracrine factors secreted by EC, while the osteoinductive properties of EC are mediated by the Notch signaling pathway, which can be activated only upon a physical contact of EC with OB. Indeed, in the direct co-culture, the knockdown of Notch1 and Notch3 receptors in EC has an inhibitory effect on the OB osteogenic differentiation, whereas activation of Notch by intracellular domain of either Notch1 or Notch3 in EC has an inductive effect on the OB osteogenic differentiation. Conclusion The data indicate the dual role of the endothelium in regulating osteogenic differentiation and highlight the unique role of the Notch signaling pathway in inducing osteogenic differentiation during cell-to-cell interactions. The findings of the study emphasize the importance of intercellular communication in the regulation of osteoblast differentiation during bone development and maintenance. Graphical Abstract