Clinical and Translational Medicine最新文献

A central hurdle limiting the success of T-cell-based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single-cell multiomics has fundamentally revised the once-prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor-exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data-spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)-proteomic layers-to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T-cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms. KEY POINTS: This review is the first to integrate multi-omics evidence for constructing a dynamic regulatory map of T-cell exhaustion. It highlights the critical cross-omics synergistic mechanisms, such as metabolic reprogramming influencing epigenetic remodeling to drive cell fate. The multi-omics perspective presented directly informs novel therapeutic strategies.

Background: Acute leukaemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) within the mitotic deacetylase complex (MiDAC) as a previously unrecognised epigenetic regulator crucial for leukaemic cell survival and elucidate its mechanistic and translational significance.

Methods: Using cellular, biochemical, and genetic perturbations, coupled with validation in multiple in vivo leukaemia mouse models, we characterised DNTTIP1's role in acute leukaemia. An integrated multi-omics analysis incorporating RNA-seq, cleavage under targets and tagmentation (CUT&Tag) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that DNTTIP1 recruits histone deacetylase 1/2 (HDAC1/2) to silence BCL2-modifying factor (BMF) and drive leukaemogenesis, validated by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR). Drug synergy assays identify poly(ADP-ribose) polymerase (PARP)/HDAC/BCL2 inhibitor combinatorial efficacy.

Results: DNTTIP1 depletion impaired MiDAC recruitment in acute leukaemia, leading to histone H3 lysine 27 (H3K27) hyperacetylation at the BMF promoter and reactivating this effector. Upregulated BMF disrupted BCL2-mediated survival, triggering coordinated autophagy and apoptosis. Combined HDAC1/2 and BCL2 inhibition exerts synergistic anti-leukaemic effects, a therapeutic strategy currently under clinical evaluation. Further, PARP inhibition profoundly enhanced this synergy by impairing DNA damage repair, unveiling a novel triple-combination strategy.

Conclusions: Our work defines the DNTTIP1‒HDAC1/2‒BMF axis as a pivotal epigenetic vulnerability in acute leukaemia and provides preclinical rationale for targeting this axis. These findings offer a validated biological framework for advancing this targeted combination therapy into clinical trials.

Key points: DNTTIP1 is overexpressed in acute leukaemia and associated with poor prognosis. DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to silence BMF and inhibit leukaemic cell death. Pharmacological disruption of the DNTTIP1-HDAC1/2-BMF axis impairs leukaemogenesis.

Background: Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), but the underlying mechanisms of this transition remain unclear. While TIMP2 is a known biomarker for AKI, its direct pathogenic role in the AKI-CKD transition has not been fully elucidated.

Methods: TIMP2 expression was evaluated in multiple murine models, including unilateral ischemia-reperfusion injury (UIR), unilateral ureteral obstruction (UUO), and cisplatin-induced nephropathy. To investigate its function, we employed a tubule-specific, inducible TIMP2 knockout mouse model (Ksp-CreERT2; TIMP2fl/fl) and a tubular overexpression model.

Results: TIMP2 was significantly upregulated during the AKI-CKD transition across all tested models. Tubule-specific deletion of TIMP2 markedly attenuated renal fibrosis, suppressed senescence-associated secretory phenotypes (SASP), and promoted tubular repair. Conversely, TIMP2 overexpression exacerbated cellular senescence and fibrotic remodeling. Mechanistically, TIMP2 was found to bind to the Wnt co-receptor LRP6, promoting its phosphorylation and subsequent β-catenin signaling activation, a process independent of its canonical matrix metalloproteinase (MMP) inhibitory function.

Conclusions: TIMP2 is a central mediator of maladaptive repair that links cell senescence and fibrotic reprogramming via the LRP6/β-catenin pathway. These findings suggest that TIMP2 serves not only as a biomarker but also as a potential therapeutic target for mitigating the AKI-CKD transition.

Highlights: TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence. Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function. TIMP2 activates Wnt/β-catenin signalling by binding to LRP6 via an MMP-independent mechanism.

Lysozyme (LYZ) is a naturally occurring antimicrobial protein first discovered in the 1920s. As a key component of innate immunity, its antimicrobial effects and immunomodulatory functions in bacterial defence have been extensively characterized. However, emerging evidence since the 1950s has revealed its complex involvement in tumour progression, with conflicting reports of both tumour-suppressive and tumour-promoting effects across different cancer types. A critical knowledge gap remains in understanding the mechanistic basis for this duality, exacerbated by reliance on single-omics approaches and small cohorts in previous studies. This review focuses on mammalian C-type LYZ (referred to as LYZ hereafter unless specified) and integrates multi-omics data (transcriptomics and proteomics) with clinical and mechanistic research to systematically dissect its dual roles in cancer. By analysing cross-cancer heterogeneity through multi-omics perspectives, we emphasize its dual promise as both a prognostic biomarker and an actionable therapeutic target, aiming to provide new insights for precision oncology. KEY POINTS: LYZ is a multi-functional secreted factor that encompasses both antibacterial and immunomodulatory functions. Emerging evidence highlights its complex role in tumour progression by directly influencing tumour cells and modulating the immune microenvironment. LYZ is a promising potential biomarker and therapeutic target in some cancers.