Molecular biomedicine最新文献

Insulin is an important endocrine peptide hormone with pleiotropic effects on metabolic regulation and cellular growth. Insulin resistance (IR), characterized by insensitivity of metabolic tissues to insulin stimulation, has emerged as a major impediment to overall metabolic health. Triggered by multiple environmental factors and genetic predisposition, IR paves the way for several related diseases, including metabolic associated diseases, cardiovascular diseases and cancer. Of note, the liver plays a central role in whole-body metabolism and is the portal encountering high concentrations of insulin. Excess glucose, lipids and the compensatory hyperinsulinemia resulting from IR may collectively impose a huge burden on the liver, driving the progression of chronic liver diseases and fostering a pro-carcinogenic environment by increasing mutagenic susceptibility and angiogenic dysregulation. Better understanding of this mechanistic link is important to highlight the underestimated role of IR in progressive diseases and may contribute to stratified diagnosis and treatment. This review summarizes the risk factors and molecular mechanisms of IR, with a specific focus on its role in carcinogenesis, taking hepatocellular carcinoma (HCC) as an example. Finally, we discuss the effective lifestyle and pharmacological interventions for IR and emphasize the necessity of incorporating IR management into the prevention, stratified diagnosis and treatment of HCC.

Tubular injury during acute kidney injury (AKI) is a major determinant of chronic kidney disease (CKD) progression, yet the molecular mechanisms underlying tubular protection remain incompletely understood. Here, we identify the matricellular protein SPARC-related modular calcium-binding 2 (SMOC2) as a previously unrecognized protective regulator of tubular injury. Although SMOC2 has been implicated in renal fibrosis through fibroblast activation, its role during AKI remains unknown. We show that SMOC2 expression is rapidly and robustly induced in renal tubules following exposure to aristolochic acid I (AAI) or cisplatin. Unexpectedly, SMOC2 knockout mice exhibited aggravated tubular injury, increased DNA damage and apoptosis, and worsened renal function in both AAI- and cisplatin-induced AKI models, whereas recombinant SMOC2 (rSMOC2) treatment markedly ameliorated AAI-induced tubular injury. Furthermore, in an AAI-induced AKI-to-CKD model, SMOC2 deficiency exacerbated renal fibrosis, linking early tubular protection to long-term outcomes. Mechanistically, transcriptomic profiling and biochemical analyses revealed that SMOC2 suppresses aberrant G1/S cell cycle progression by restraining the CCND1-CDK4/6 axis through its interaction with integrin β3 (ITGB3), thereby arresting tubular cells in the G1 phase and facilitating DNA repair. This interaction depends on the cooperation of multiple structural domains rather than a single motif. Notably, pharmacological inhibition of CDK4/6 with palbociclib phenocopied the protective effects of SMOC2, with post-injury treatment providing superior protection, thus defining a druggable downstream pathway. Collectively, our findings uncover a previously unappreciated cytoprotective role of SMOC2 in AKI and establish the SMOC2-ITGB3-CCND1-CDK4/6 signaling axis as a potential therapeutic target to prevent AKI progression and its transition to CKD.

Nonalcoholic steatohepatitis (NASH) is a metabolic disease characterized by hepatic steatosis and inflammation among other features. Dysregulated lipid metabolism is crucial in the pathogenesis of NASH. However, its regulatory mechanisms remain intricate and poorly elucidated. Hepatic stellate cells (HSCs) have been reported to contribute to hepatocellular lipid metabolism dysregulation and aggravate NASH progression. However, the potential mechanisms remain unclear. Here, we demonstrate that hydrogen peroxide-inducible clone 5 (Hic-5), which is highly expressed in HSCs within the liver, is elevated in NASH patients and mouse models. Hic-5 deficiency alleviates hepatic steatosis, and liver metabolomics revealed reduced fatty acid levels. Meanwhile, RNA-sequencing revealed that Hic-5 deficiency increases AMPK phosphorylation. Additionally, HSC-specific overexpression of Hic-5 exacerbates NASH severity. Co-culture experiments indicated that Hic-5 increases hepatocellular fatty acid synthesis. Cellular transcriptomic analysis and validation revealed that prostaglandin E2 (PGE2), secreted by HSCs, mediates hepatocellular fatty acid synthesis. Mechanistically, the N-terminal domain of Hic-5 binds c-Src, leading to phosphorylation of PTEN, which is bound to the C-terminal domain. This event subsequently induces phosphorylation and nuclear translocation of the transcription factor SP1, ultimately increasing PGE2 secretion. Finally, Hic-5 promotes hepatocellular fatty acid synthesis by activating the PGE2-EP4 axis. Pharmacological inhibition of EP4 in HSC-specific Hic-5 overexpression mice fed with HFD diet (HFD) significantly attenuated NASH progression. These findings increase our understanding of molecular mechanisms linking hepatic lipid metabolism dysregulation and may offer therapeutic potential for treating NASH.

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine and participates in multiple cellular processes, such as cell development, proliferation, epithelial mesenchymal transition (EMT), and immune responses through SMAD-dependent or SMAD-independent signaling pathways. Notably, TGF-β signaling plays a dual role in tumors, acting as a potent tumor suppressor during early tumorigenesis by inducing apoptosis or cell-cycle arrest while promoting tumor transformation, progression and metastasis in advanced stage through multidimensional mechanisms. Moreover, it is abundant and functions as a master immune checkpoint in the tumor microenvironment (TME), fostering the development of numerous targeted therapies to rectify its aberrant activity in tumors in the past decades. Thus, a comprehensive overview of the pathologic roles, molecular mechanisms and therapeutic potentials of TGF-β signaling in tumors will benefit both the basic and clinical cancer research. Here, we review the complex biology and context-dependent functions of the TGF-β superfamily in regard to tumor, highlighting how it regulates the latter's development, growth, and dissemination by mainly targeting tumor cells, tumor-associated fibroblasts and various immune cells. We also summarize recent advances in the preclinical and clinical development of different types of TGF‑β‑targeting agents, and discuss their therapeutic potentials and challenges as well as approaches to improve the safety and efficacy of TGF-β pathway-targeted therapy in cancers. Through the summary of known knowledge and the latest updates, this review may provide a general picture on the biological functions of TGF-β in tumors, and facilitate the clinical implications of TGF-β-targeted therapy in tumor patients.

Chimeric antigen receptor (CAR)-engineered cell therapies represent a significant breakthrough in immunotherapy, initially in cancer and now expanding into diverse clinical fields. While originally developed for oncology, these platforms are increasingly being adapted for non-malignant conditions such as autoimmune disorders, infectious diseases, fibrosis, ageing-related issues, and organ transplants. This review details the evolution and diversification of CAR modalities- including CAR-T, CAR-NK, CAR-macrophages, and CAR-NKT cells- as well as emerging next-generation designs. It describes the key aspects of CAR structure, signalling pathways, and manufacturing, emphasising their application in treating hematologic and solid tumours, while considering challenges such as the tumour microenvironment (TME). The review also discusses expanding uses beyond cancer- such as CD19/BCMA-targeted CAR-T cells achieving long-term remission in lupus and rheumatoid arthritis without ongoing immunosuppression, CAR-NK approaches targeting HIV, CAR-Tregs enhancing transplant tolerance, and senolytic CARs reducing tissue fibrosis. Up-to-date research through 2025 is summarised to evaluate efficacy, safety, and adverse events, noting that CAR therapies show lower cytokine release syndrome (CRS) in autoimmune diseases. Innovations like off-the-shelf allogeneic products and logic-gated CARS are highlighted, alongside ongoing challenges such as manufacturing complexity, high costs, and antigen escape. Trials like KYV-101 for multiple sclerosis demonstrate continued progress and the potential of these therapies to translate into clinical practice. Overall, CAR-engineered treatments enable precise, programmable immune modulation, paving the way for advanced therapies across an expanding array of diseases.

Despite the precise targeting of radiation therapy, collateral damage to adjacent healthy tissues remains an inevitable consequence. Currently, no effective clinical intervention exists to prevent or alleviate these adverse effects. To address this issue, our study established a whole-abdominal irradiation (WAI) model using C57BL/6J mice to investigate the systemic effects of ionizing radiation (IR) on the gut and other organs. Results confirmed that IR not only causes significant intestinal damage but also induces cardiac injury and cognitive dysfunction through remote effects. Ergothioneine (EGT), a naturally occurring dietary sulfur compound, has garnered significant attention in recent years for its unique functions in antioxidant, anti-inflammatory, and metabolic regulation. Our findings reveal that EGT significantly mitigates IR-induced structural damage to the intestine, preserves crypt-villus architecture, restores goblet cell numbers, and reduces systemic inflammation. Furthermore, EGT modified post-IR gut microbiota composition by decreasing the relative abundance of Candidatus_Soleaferrea and downregulating calcium voltage-gated channel subunit alpha1 C (Cacna1c) expression. EGT alleviated WAI-induced cardiac and cognitive dysfunction through the gut-heart and gut-brain axes. EGT also ameliorated dextran sulfate sodium (DSS)-induced colitis and enhanced intestinal barrier function. Our findings identify EGT as a novel multi-organ radioprotective agent that acts through microbiota modulation and Cacna1c regulation, providing a viable strategy for improving radiotherapy safety and efficacy.

Acute myocardial infarction (AMI) remains a leading cause of global cardiovascular morbidity and mortality. Limitations in current diagnostic methods hinder early detection and intervention, creating an urgent need for novel early diagnostic biomarkers. This study employed an integrated multi-omics approach, combining metabolomics, Mendelian randomization (MR), and transcriptomics data to identify potential AMI biomarkers. Plasma metabolomic profiling revealed 174 differentially abundant metabolites. Subsequent MR analysis pinpointed a key causal metabolite, L-arachidoyl carnitine (carnitine C20:0). Genes associated with this metabolite were retrieved from the GeneCards database and cross-referenced with differentially expressed genes from the GEO database, leading to the identification of 10 candidate biomarker genes: ACSL1, PYGL, DYSF, MGAM, SLC7A7, SULF2, KCNJ2, CYP1B1, NCF2, and SLC22A4. By constructing and evaluating 80 machine learning models, the Enet[alpha = 0.1] model was determined to have the optimal diagnostic performance. The diagnostic potential of these ten genes was further corroborated by logistic regression with tenfold cross-validation. Additionally, immune cell infiltration analysis using the CIBERSORT algorithm uncovered potential associations between the candidate genes and specific immune cell subpopulations. In conclusion, this sequential multi-omics investigation successfully identifies and validates 10 gene biomarkers related to AMI, offering new perspectives for early precision diagnosis and insights into the disease's pathogenesis, alongside potential therapeutic targets.

Fibroblast growth factor 1 (FGF1), a well-characterized member of the FGF family, effectively lowers blood glucose levels in animal models of type 2 diabetes by stimulating glucose uptake. However, its significant mitogenic potential poses a major challenge for clinical application. Here, we present engineered variants of FGF1 designed to dissociate its potent glucose-lowering effects from its undesired proliferative activity, aiming for a future therapeutic agent for type 2 diabetes. Through a series of rational mutations focused on modulating receptor binding and heparan interactions, coupled with enhanced thermodynamic stability, we developed two lead FGF1 variants. Comprehensive in vitro studies confirmed that these variants exhibit significantly reduced mitogenic potential across various cell types compared to wild-type FGF1. Specifically, one variant showed profound loss of proliferation due to disrupted FGFR binding, while the other displayed attenuated mitogenicity linked to decreased heparin affinity. Critically, both fully maintained potent glucose-lowering properties in db/db mice without inducing hypoglycemia or changes in body weight. Furthermore, these engineered proteins demonstrate superior thermodynamic stability and markedly improved pharmacokinetic profile, critical attributes for drug development. Our findings highlight a successful strategy to uncouple the therapeutic benefits of FGF1 from its mitogenic side effects, offering promising, stable, and safe protein-based drug candidates for type 2 diabetes treatment.

Radiation-induced injury remains a significant challenge in the radiotherapy of cancer patients. Ionizing radiation causes various cellular and molecular damages, leading to both acute and chronic organ dysfunction. Its impact extends beyond interrupting standard treatment protocols and adversely affects the quality of life. Therefore, understanding the mechanisms underlying radiation-induced injury and identifying effective treatment strategies are crucial. In this review, we summarize the recent advances in the molecular and cellular mechanisms of radiation-induced injury across various organs and systems, particularly in the lung, gastrointestinal system, brain, skin, and bone. We highlight the roles of oxidative stress, DNA damage response, mitochondrial dysfunction, and epigenetics in radiation pathology, and summarize the relevant signaling pathways and cellular responses involved in radiation damage. Additionally, we discuss the common symptoms, risk factors, and current diagnostic strategies of radiation-induced injuries. Furthermore, this article provides an in-depth review of effective clinical treatments, elucidates their mechanisms of action, and highlights emerging therapeutic approaches, such as stem cell therapy, nanomedicine, and exosome-based interventions, in clinical practice. Despite significant advances in understanding radiation-induced injury, challenges remain in translating molecular insights into effective therapies. The review concludes with a call for integrated, precision medicine-based approaches to better manage radiation-induced injuries and improve patient outcomes.