Circadian rhythm is an endogenous timekeeping system that enables organisms to adapt to light-dark cycles, feeding rhythms and environmental changes. At the molecular level, circadian oscillation is maintained by transcriptional-translational feedback loops composed of clock circadian regulator(CLOCK), basic helix-loop-helix ARNT like 1(BMAL1), period(PER), cryptochrome(CRY), REV-ERB nuclear receptor(REV-ERB)and retinoic acid receptor-related orphan receptor(ROR). The liver is a central organ for metabolism, detoxification and immune regulation, and also a typical peripheral clock organ. Hepatic glucose and lipid metabolism, bile acid synthesis, xenobiotic metabolism, mitochondrial oxidative phosphorylation, antioxidant defense and immune responses exhibit robust circadian oscillations. Accumulating evidence indicates that circadian disruption contributes to a variety of liver injury-related disorders, including metabolic dysfunction-associated steatotic liver disease, drug-induced liver injury, alcoholic liver disease, cholestatic liver injury, hepatic ischemia/reperfusion injury and liver fibrosis. Mechanistically, circadian clocks regulate liver injury by modulating insulin resistance, oxidative stress, inflammatory responses, autophagy, endoplasmic reticulum stress and multiple forms of regulated cell death. Conversely, hepatic injury-associated lipid accumulation, hypoxia, inflammatory cytokine release and metabolic reprogramming may disturb local hepatic clocks, forming a vicious cycle of circadian disruption, metabolic imbalance and aggravated liver injury. This review summarized the molecular basis of circadian rhythm and its role in hepatic metabolic homeostasis, highlighted the mechanistic links between circadian clocks and liver injury, and discussed potential therapeutic strategies based on chronobiology.

RNA and DNA viral infections pose a serious threat to human health. As the hosts first line of defense against viral invasion, the innate immune system recognizes pathogen-associated molecular patterns(PAMPs)and damage-associated molecular patterns(DAMPs)through pattern recognition receptors, thereby initiating downstream signaling pathways that induce the secretion of type I interferons and inflammatory cytokines, rapidly activating the antiviral immune response. RLRs, cGAS-STING, and TLRs constitute three core signaling pathways that mediate antiviral innate immunity. RIG-I and MDA5, members of the RLRs family, specifically recognize cytoplasmic RNA viruses and activate downstream signaling through the MAVS adaptor protein. The cGAS-STING pathway primarily detects cytoplasmic viral DNA and activates the interferon response pathway by synthesizing the second messenger cGAMP. Endosomal-localized TLR3/7/8/9 recognize viral nucleic acids and initiate immune signaling through TRIF- or MyD88-dependent pathways. However, excessive activation of immune signals can lead to a massive accumulation of inflammatory factors, causing irreversible damage to the tissues and cells; therefore, the regulation of immune homeostasis is crucial for the bodys defense against viral infections. Ubiquitination is one of the key post-translational modifications that regulate the innate immune response against viruses. Through the action of various ubiquitin ligases and deubiquitinases, ubiquitination is applied to the core receptors and key proteins in these pathways, thereby precisely regulating immune signaling. This article reviews the regulatory roles of ubiquitination in the three major classical antiviral innate immune pathways-RLRs, cGAS-STING, and TLRs, and provides a theoretical basis for antiviral immunotherapy.

Aberrantly localized or inappropriately exposed DNA potently activates innate immune signaling pathways. During infection, nucleic acids from pathogens such as viruses and bacteria serve as critical pathogen-associated molecular patterns(PAMPs). Under pathological conditions, host-derived DNA, including mitochondrial DNA and chromosomal DNA, can also act as danger-associated molecular patterns(DAMPs)to elicit potent inflammatory responses. Cyclic GMP-AMP synthase(cGAS)is the primary intracellular DNA sensor. Upon activation, cGAS synthesizes the second messenger cGAMP to initiate STING-dependent signaling cascades, leading to the production of type I interferons and proinflammatory cytokines, and plays important roles in various pathological processes including infectious diseases, aging, cancer, and autoimmune diseases. This review systematically discusses the regulatory mechanisms of cGAS activation from four perspectives: DNA features, cGAS regulation, cGAMP dynamics, and DNA accessibility to cGAS, aiming to open new therapeutic avenues for acute and chronic inflammation associated with diverse human diseases.

TANK-binding kinase 1(TBK1)was initially characterized as a central component of antiviral innate immunity, but is now recognized as a broader regulator of immune homeostasis, selective autophagy and cellular adaptation to metabolic stress. This functional diversity arises from multiple layers of control that extend beyond kinase activation itself. TBK1 is recruited to distinct signaling platforms formed by STING, MAVS and TRIF, where subcellular localization, adaptor composition and post-translational modifications determine its activation kinetics and access to substrates. In parallel, metabolic and stress-associated signals reshape TBK1 activity, linking cellular state to immune output. Through these regulatory mechanisms, TBK1 coordinates type I interferon production, inflammatory responses and pathogen clearance, while also contributing to mitochondrial quality control and metabolic adaptation. Disruption of this balance has markedly different consequences across tissues and disease settings: insufficient TBK1 activity can impair host defense and neuronal integrity, whereas persistent or aberrant signaling can sustain inflammation, metabolic dysfunction and tumor cell survival. Here, we discuss the structural basis and multilayered regulation of TBK1, examine how spatial and metabolic cues shape its immune functions, and consider how context-dependent changes in TBK1 signaling contribute to infectious, autoimmune, metabolic, malignant and neurological diseases. Viewing TBK1 as a dynamically regulated signaling hub, rather than solely as an antiviral kinase, provides a framework for reconciling its diverse and sometimes opposing functions in physiology and disease.

Chronic kidney disease(CKD)poses a severe global public health burden, yet its pathogenesis remains incompletely understood and current therapies are limited, with poor prognosis. In particular, conventional anti-fibrotic strategies have shown limited success in clinical translation. Growing evidence suggests that disruption of the renal tissue microenvironment represents a central driver of kidney injury and disease progression. In this article, we highlight the emerging concept that restoration of microenvironmental homeostasis is fundamental to successful renal repair, delineate the cellular and molecular networks that coordinate injury responses, identify key therapeutic targets governing kidney regeneration and fibrosis, and discuss innovative strategies to promote adaptive repair while limiting chronic tissue remodeling. These advances redefine current concepts of CKD pathogenesis and provide a mechanistic foundation for the development of next-generation precision therapies aimed at restoring renal homeostasis and regenerative capacity.

Pancreatic islets are highly organized micro-organs composed of endocrine cells, immune cells, microvasculature, and extracellular matrix components, and their homeostasis relies on finely coordinated and dynamic interactions among multiple cell types. Increasing evidence indicates that diabetes is not solely attributable to β-cell dysfunction, but is also closely associated with disrupted intercellular communication, remodeling of the immune microenvironment, and metabolic stress within the islet. Focusing on islet homeostasis in the context of glucose and lipid metabolism, this review summarizes the regulatory circuits involving β-δ cells, β-α cells, and islet macrophages, with particular emphasis on the effects of hyperglycemia, lipid overload, inflammatory responses, and microenvironmental remodeling on islet function. We further discuss the major classes of glucose-lowering therapies from the perspective of their effects on islet homeostasis.

Ferroptosis is an iron-dependent, regulatory form of cell death driven primarily by lipid peroxidation, and it is distinct from apoptosis, necrosis, and pyroptosis in terms of morphology, regulatory mechanisms, biochemistry, and genetics. Over the past decade, studies have shown that ferroptosis, as a key hub linking intracellular iron metabolism, amino acid metabolism, lipid metabolism, and glucose metabolism, is widely involved in the clinical and pathological processes of neurodegenerative diseases(such as Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis)and multi-organ injury(ischemia-reperfusion injury, liver injury, kidney injury, and cardiac injury). This article systematically reviews the core regulatory network of ferroptosis-iron metabolism disorders, imbalance of the antioxidant defense system, and the lipid peroxidation cascade-and focuses on its pathological significance in the central nervous system and multiple peripheral organ injuries. On this basis, it systematically reviews the current status of ferroptosis inducers and inhibitors in clinical development, and further analyzes the challenges faced in targeting ferroptosis for intervention in related diseases, including cell-type specificity, tissue specificity, and drug stability and safety. It also further discusses the application prospects of gene therapy technologies and precise drug delivery systems in the treatment of ferroptosis-related diseases.

The gut microbiota influences antitumor immunity and responses to immune checkpoint inhibitors, while diet shapes microbial functions by altering nutrient availability and ecological niches. This review focused on microbial mechanisms associated with dietary fiber and amino acids, and on the effects of short-chain fatty acids, inosine, and bile acids on dendritic cells, T cells, and natural killer/natural killer T(NK/NKT)cells. Microbial antigens and innate immune signals were discussed as a complementary pathway. We distinguish studies establishing a diet-microbiota-immunity causal chain in animal models from those supporting only the microbiota- or metabolite-immunity link, and from observational associations in humans. High-fiber diets and selected amino acid interventions have relatively complete mechanistic support in animals, whereas studies of inosine, several bile acids, and microbial antigen cross-reactivity mainly establish downstream mechanisms and cannot directly demonstrate the antitumor effects of a specific diet. Across representative dietary interventions, we propose an integrated assessment of dietary substrates, microbial functions, metabolite production or nutrient consumption, spatial exposure, and target cells. Randomized dietary trials are needed to establish benefits during cancer immunotherapy.

The loss-of-function mutation of CUL4B gene is one of the most common pathogenic genes in X-linked mental retardation(XLMR)syndrome. In addition to intellectual disability, patients also have symptoms such as speech delay, motor delay, seizures, short stature, brachydactyly, obesity, increased monocyte counts in peripheral blood, and hypogonadism, indicating that the CUL4B gene plays a broad role in the development and homeostasis maintenance of various tissues and organs. Analyzing the pathogenic mechanisms of CUL4B gene loss-of-function mutations leading to the above symptoms not only helps to understand the function of this gene, but also provides new insights for the treatment of this disease and related diseases. This article will discuss the pathological mechanisms and clinical significances of CUL4B gene loss-of-function mutations in areas such as intellectual disability, epilepsy, metabolism, skeleton, and immunity.

Organoids are three-dimensional cell culture systems generated in vitro from primary tissue-derived cells, pluripotent stem cells, or adult stem cells. They are typically composed of multiple tissue-specific cell types and exhibit self-renewal, self-organization, and selected structural and functional characteristics of native tissues. Organoids can retain patient- or disease-specific genetic backgrounds and recapitulate disease phenotypes in terms of cellular composition, tissue architecture, signaling pathways, metabolic states, and multidimensional omics features. They therefore provide valuable experimental platforms for disease modeling, mechanistic investigation, drug screening, safety assessment, and prediction of individualized therapeutic responses. With advances in culture systems, bioengineering technologies, and multi-omics analytical approaches, organoids are no longer limited to the morphological reconstruction of individual tissues. Instead, they are increasingly being developed into precision medicine platforms that integrate disease modeling, drug screening, toxicity evaluation, mechanistic analysis, and personalized treatment-response prediction. Focusing on organoid-based disease modeling and intervention strategy development, this review summarizes major applications of organoids in disease research, including immune-integrated organoids, vascularized organoids, multicellular models of neural-stromal interactions, as well as microfluidic systems, organ-on-chip platforms, and multi-organ interaction systems. Using complex diseases such as metabolic liver disease, chronic kidney disease, and Alzheimers disease as examples, we discuss the roles of organoid models in disease phenotype recapitulation, reconstruction of pathological microenvironments, and elucidation of inter-organ communication mechanisms. In addition, this review highlights emerging interdisciplinary technologies that are accelerating organoid research and application, including three-dimensional bioprinting, single-cell sequencing, spatial transcriptomics, artificial intelligence-assisted drug screening, and virtual cell modeling. Finally, key future directions are discussed, including improvements in organoid maturation, standardization, scalability, and multimodal data integration.

Metabolic reprogramming of the tumor microenvironment(TME)is a critical driver of malignant progression, immune evasion, and therapeutic resistance in cancer. Among the most prominent metabolic alterations, aerobic glycolysis, known as the Warburg effect, engages in bidirectional crosstalk with antitumor immunity. Even under normoxic conditions, tumor cells aberrantly activate glycolytic pathways and exploit multiple remodeling mechanisms-including glucose competition, lactate accumulation, extracellular acidification, and lactylation-to establish an immunosuppressive TME. This metabolic rewiring suppresses the activation, infiltration, and cytotoxic functions of effector immune cells, while simultaneously promoting the recruitment and functional maintenance of immunosuppressive populations such as regulatory T cells(Tregs), tumor-associated macrophages(TAMs), and myeloid-derived suppressor cells(MDSCs), thereby facilitating immune evasion and attenuating the efficacy of immunotherapies. Conversely, the activation, differentiation, and homeostatic maintenance of immune cells are strictly dependent on specific glycolytic programs, and the differential metabolic adaptability among immune cell subsets profoundly influences the immune equilibrium within the TME. Accumulating evidence indicates that tumor glycolytic pathways engage in positive feedback regulatory loops with classical immunosuppressive axes, including the programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1)and the ectonucleoside triphosphate diphosphohydrolase 1/ecto-5'-nucleotidase(CD39/CD73)-adenosine pathways, which may represent a pivotal mechanism underlying the limited efficacy of immune checkpoint inhibitors. In recent years, targeted modulation of key glycolytic molecules, improvement of the metabolic-immune landscape of the TME, and combination with immunotherapy have emerged as important research directions in precision oncology. This review systematically summarizes the core molecular regulatory mechanisms of the Warburg effect, delineates the multiple pathways through which glycolytic reprogramming induces immunosuppression, characterizes the glycolytic metabolic adaptations of distinct immune cell subsets, and elucidates the interplay between glycolytic metabolism and immune signaling pathways. Furthermore, we review glycolytic-targeted intervention strategies and relevant clinical progress, analyze the major challenges hindering clinical translation of current research findings, and discuss future directions leveraging emerging technologies such as spatial multi-omics and cell metabolic engineering, with the aim of providing a theoretical foundation for the development and clinical application of metabolism-immunity combination therapeutic strategies.