Cell Reports Medicine最新文献

Approximately 20% of acute myocardial infarction (AMI) patients with multivessel disease experience adverse outcomes after complete revascularization. We aim to investigate the underlying metabolic mechanism of ischemia-reperfusion injury responsible for abnormal hemodynamic stresses in high-risk patients undergoing complete revascularization. Elevated preoperative serum levels of long-chain acylcarnitine (LCAC) 16:1 are associated with an increased risk of poor prognosis following complete revascularization. Multi-omics analyses reveal that reperfusion injury activates fatty acid degradation, and carnitine palmitoyltransferase 1A (CPT1A) is identified as a key regulator of LCACs in the interaction network in porcine models. In the early stages of reperfusion injury in non-culprit lesions, the release and prolonged elevation of circulating LCACs primarily depend on the activation of endothelial CPT1A through hemodynamic injury, which can be reduced using an inhibitor (etomoxir). Excess LCACs enter cardiomyocytes via the organic cation transporter 2, leading to imbalanced mitochondrial quality control and causing cardiomyocyte death.

The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67⁺ immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3⁺ immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals. These findings link exercise training to cancer risk reduction by alleviating inflammation, decreasing immunosenescence, and improving the reservoirs of overall immunity for cancer prevention.

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of EGFR TKI plus ALPP antibody conjugated with monomethyl auristatin F enhances tumor killing in osimertinib-sensitive and -resistant LUAD models compared to either treatment alone. Our findings support a combination therapy involving an EGFR inhibitor together with an ALPP antibody drug conjugate for EGFR-mutated LUADs.

Adult neurogenesis plays a crucial role in maintaining brain homeostasis and can respond to neurogenic injuries. However, the adult mammalian spinal cord has extremely limited intrinsic neurogenic ability. Here, we show that in vivo astrocyte-to-neuron conversion can regenerate functional neurons after spinal cord injury (SCI) through CRISPRa-mediated activation of endogenous transcription factors Ngn2 and Isl1. Lineage tracing confirms that the origin of these induced neurons is reactive astrocytes, rather than endogenous neurons. Furthermore, these induced neurons express specific markers of motor neurons and glutamatergic neurons and form synaptic connections with ascending and descending spinal pathways. Importantly, astrocyte-to-neuron conversion promotes propriospinal axon regeneration, improves the neuromuscular junction (NMJ) morphology and function of muscle, and finally promotes motor functional recovery after SCI. In summary, our results would contribute to resolving the controversy surrounding lineage reprogramming and demonstrate that in vivo cell conversion may be a potential therapeutic strategy for treating SCI.

After the primary response, circulating memory CD4⁺T effector and T regulatory (Treg) cells regulate recall responses, typically impaired in allergy. We discovered distinct metabolomes of these cells in humans, differentially enriched in phenylalanine-related metabolites. Energy metabolism assessment in in vitro and ex vivo single-cell analyses revealed that increased intracellular L-phenylalanine boosts glycolysis while limiting oxidative phosphorylation (OXPHOS) in CD4⁺T, memory CD4⁺T, and Th2 cells, but not in Th1, Th17, or Treg cells. L-phenylalanine also restrains proliferation of memory CD4⁺T, Th2, and Th17 cells in an IL4I1-dependent manner and limits Th2 differentiation via inhibition of STAT6 and mechanistic target of rapamycin (mTOR) signaling. RNA sequencing, metabolomics, flow cytometry, and proteomics, validated both in vitro and across patient cohorts, revealed impaired LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy, with increased intracellular processing accompanied by expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in Th2 cell development, energy metabolism, and function.

The clinical diagnosis of epilepsy is predominantly based on history taking, morbidity records, and imaging during seizures. The emergence of proteomics has enhanced disease marker detection and potential drug target identification. We perform a longitudinal survival analysis of 2,920 plasma proteins and epilepsy onset, utilizing plasma proteome data from 52,372 UK Biobank participants (440 incident cases). We identify 103 proteins with significant associations with epilepsy, with neurofilament light polypeptide (NEFL) (hazard ratio [HR] [95% confidence interval (CI)]: 2.13 [1.85-2.46]) and growth differentiation factor 1 (GDF15) (1.82 [1.60-2.07]) exhibiting the strongest correlations. Enrichment and network analyses uncovered the pivotal role of the immune response and pinpointed four central hubs. Furthermore, 103 screened proteins are significantly associated with brain regions implicated in epileptogenesis and show stronger correlation with stress-related events than genetic predisposition. We investigate the predictive ability of top-ranked proteins for future epilepsy risk and their potential as drug targets. These findings are crucial for identifying early biomarkers and optimizing therapeutic strategies.

Dendritic cells (DCs) are potent antigen-presenting cells, key for inducing anti-tumoral immune responses in the tumor microenvironment (TME) and tumor-draining lymph nodes. Within the TME, immunosuppressive signals often render DCs dysfunctional, hindering their propagation of T cell-mediated cancer cell death and tumor regression. DC-based immunotherapy has been investigated for over two decades, aiming to induce anti-tumor immunity by directly delivering DCs or antigens through vaccination or by enhancing the anti-tumor functions of existing DCs within the TME. Despite some progress, clinical benefit in many patients is still limited. As our understanding of the complex interactions that occur in the TME deepens and new technologies emerge, novel DC immunotherapy strategies are continuously being developed and advanced into clinical trials. This review provides an updated summary of the latest advances in these therapies, identifying trends that correlate with successful outcomes, as well as the challenges still being faced in the field.

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable disease, and the median progression-free survival reaches 2.9 months. This study represents the most extensive molecular characterization of RMC to date, identifying TROP2 and other potential therapeutic targets. Sacituzumab govitecan demonstrates potential clinical benefit, warranting further evaluation in prospective trials to confirm its efficacy and explore additional targets identified herein.

Ferroptosis is recognized as a form of regulated cell death characterized by iron-dependent lipid peroxidation and significant immunogenic properties. However, we observe that the hypoxic tumor microenvironment (TME) of solid tumors severely limits ferroptosis induction and antitumor immune responses, while simultaneously promoting programmed death-ligand 1 (PD-L1) expression, thereby further compromising tumor immunotherapy. Herein, we exploit a fluorinated prodrug-engineered nano-remodeler to reverse the hypoxic and immunosuppressive TME for enhancing ferroptosis/immunomodulation-driven antitumor therapy. The nano-remodeler is elaborately co-assembled by the disulfide-bonded fluorinated JQ1 prodrug (a PD-L1 inhibitor) and sorafenib (Sor, a ferroptosis inducer). As expected, the ferroptosis induction efficiency and antitumor immunogenicity of Sor are significantly improved due to oxygen supply in hypoxic solid tumors, resulting in a highly synergistic ferroptosis-immunotherapy with JQ1. As a result, this nano-remodeler exerts a potent tumor inhibitory effect in multiple tumor models. This study provides insights into the nanotherapeutic paradigm of tumor hypoxia intervention in multimodal ferroptosis-immunotherapy.