Dysregulation of lipid metabolism is a central hallmark of tumor cells, providing not only the energy reserves necessary for rapid proliferation but also the structural precursors required for membrane biosynthesis. RNA-binding proteins (RBPs), as central executors of post-transcriptional regulation, play an increasingly recognized role in tumor lipid metabolic reprogramming. Studies have shown that RBPs systematically regulate the mRNA stability, translation efficiency, and subcellular localization of genes related to lipid metabolism by selectively recognizing and binding to specific target RNAs, thereby coordinating lipid synthesis, lipolysis, transport, and storage to ultimately drive the remodeling of tumor metabolic networks. Although the link between RBPs and lipid metabolism has attracted growing attention, this review is organized specifically around an overview of RBPs and the perspective of RBP-targeted therapies. Adopting the classification of classical and non-classical RBPs as a unifying framework, this article systematically reviews the molecular regulatory mechanisms by which RBPs mediate lipid metabolic reprogramming in the context of lipid synthesis, degradation, transport, and storage, as well as their contributions to tumor initiation, progression, immune evasion, and microenvironment adaption, with particular attention to the functional heterogeneity of RBP-RNA regulatory axes across tumor types. Beyond mechanistic understanding, the article evaluates therapeutic strategies targeting RBPs, including molecular glues, PROTACs, and RNA-based interventions, together with their key challenges, such as drug developability, delivery specificity, and resistance mechanisms, aiming to provide a theoretical framework and cutting-edge perspectives for elucidating tumor metabolic plasticity and advancing RBP-based precision therapy.
Human pluripotent stem cells (hPSCs), comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have emerged as a versatile platform connecting developmental biology with disease modelling, drug discovery, and regenerative medicine. Their capacity for indefinite self-renewal and differentiation into derivatives of all three germ layers provides an essentially renewable source of human cells that are otherwise inaccessible from patients. In this review, we discuss the biological principles governing hPSC identity, with emphasis on the transcriptional, epigenetic, metabolic, and extracellular signalling networks that regulate pluripotency and the distinct features of naive and primed states. We further examine culture systems for maintaining pluripotency and directed differentiation strategies for generating lineage-specific cell types. The application of hPSCs to disease modelling and therapeutic discovery is considered through two-dimensional cellular models and increasingly sophisticated three-dimensional organoids and organoid-on-chip systems, which provide progressively greater tissue complexity and physiological relevance. We also highlight the integration of CRISPR-based genome editing with hPSC platforms to generate isogenic disease models, establish genotype–phenotype relationships, identify therapeutic targets, and enable precise correction of disease-associated variants. Finally, we review the emerging clinical applications of hPSC-derived cell therapies and clinical translation, which remains constrained by challenges related to genomic stability, cellular heterogeneity and maturation, immune compatibility, tumorigenicity, manufacturing, and scalability. Addressing these challenges through improved differentiation, quality control, genome engineering, and scalable manufacturing will be essential for translating the broad potential of hPSCs into safe, reproducible, and accessible clinical therapies.
Metabolites have traditionally been viewed primarily as energy sources and biosynthetic substrates for cells. However, the discovery of novel protein modifications such as lactylation, succinylation, and O-GlcNAcylation demonstrates that metabolites can also function as signaling molecules, whose activated high-energy derivatives directly drive post-translational modifications (PTMs) of proteins. The regulatory axis of ‘metabolic sensing–PTM remodeling–cellular functional reprogramming’ that emerges from this plays a significant role in the pathogenesis of tumors, immune disorders, and metabolic genetic diseases. This review centers on this regulatory axis. We first elaborate the chemical-structural basis governing metabolite-driven PTM biogenesis, followed by discussion of upstream metabolic-pathway activation and downstream regulatory outputs, including chromatin remodeling, protein phase separation and metabolic feedback circuits. Based on this, we employ cross-species comparisons to discuss the evolutionary conservation and functional divergence of this axis. This analysis clarifies several long-standing controversies, including the distinction between enzymatic and non-enzymatic modifications, the crosstalk between different modifications, the concentration thresholds required in vivo and in vitro for modification occurrence, and the strategies for validating causality. Finally, advances in technologies such as single-cell and spatial multi-omics, live-cell metabolic probes, targeted small-molecule tools, and systems modeling are discussed to explore their potential applications, aiming to provide insights for biomarker discovery and precision intervention in metabolic diseases. Central to this review is the emphasis on chemical and biophysical constraints governing metabolite-driven PTMs, which shape their occurrence, compartment-dependent enzyme-dependence, and downstream biological outputs.
Renal allograft fibrosis is a common histological endpoint after multiple injuries, rather than an independent disease entity. Despite modern immunosuppression, recurrent alloimmune injury, ischemia reperfusion injury, infection, donor and recipient related factors, and drug toxicity can converge on interstitial fibrosis and tubular atrophy. This review examines how innate and adaptive immune responses contribute to the transition from early graft injury to chronic remodeling, with particular emphasis on cellular plasticity and intercellular communication. Human single cell and spatial studies show that immune, tubular epithelial, endothelial, and stromal cells form heterogeneous, stage dependent networks rather than fixed pathogenic populations. We prioritize evidence from human kidney allografts while clearly identifying mechanisms inferred from experimental models. Established immunosuppression remains essential for preventing immune mediated graft injury, whereas regulatory T cell therapies, macrophage state modulation, cytokine blockade, and CD38 directed therapy remain investigational. None has been proven to reverse established allograft fibrosis. Future diagnosis and treatment should integrate Banff histology, donor specific antibodies, donor derived cell free DNA, urinary chemokines, and biopsy-based transcriptomics. Clinical trials should determine whether targeted immunomodulation can slow the progression of allograft fibrosis and preserve long-term graft function and survival.
Osteoarthritis (OA) is a heterogeneous whole-joint disease in which mechanical, inflammatory, metabolic, and age-related factors converge to disrupt tissue homeostasis. Mechanical loading is essential for cartilage maintenance, whereas excessive or insufficient mechanical stimulation may disrupt cartilage homeostasis depending on the loading modality, magnitude, frequency, duration, recovery conditions, and tissue context. In this review, we integrate OA mechanobiology across scales, from whole-joint load redistribution and tissue-level mechanical filtering to chondrocyte mechanosensing and intracellular responses. The mechanistic emphasis is on cartilage and chondrocytes within the broader whole-joint context of OA. We discuss how integrin-focal adhesion complexes, PIEZO1/2, TRPV4, primary cilia, the cytoskeleton, and nuclear mechanotransduction regulate matrix metabolism, mitochondrial redox homeostasis, autophagy and mitophagy, regulated cell death, and cellular senescence. We further highlight mechanical unloading, immobilization, and microgravity-related models as distinct experimental contexts and discuss epigenetic, epitranscriptomic, and ubiquitin-dependent regulation as potential mechanisms underlying persistent cellular reprogramming, while recognizing that mechanical memory after stimulus withdrawal remains insufficiently established in OA. Finally, we outline how subject-specific modeling, spatial multi-omics, joint-on-chip systems, and multimodal mechanical phenotyping may support mechanobiology-guided OA stratification and therapy. Restoring patient-specific mechanical homeostasis, rather than simply reducing loading, may provide a framework for precision management of OA.
