Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes in both physiological and pathological conditions, highlighting their adaptive plasticity and diverse functions. Under normal conditions, astrocytes modulate synaptic activity, recycle neurotransmitters, and maintain the blood-brain barrier, ensuring a balanced energy supply and protection against oxidative stress. However, in response to central nervous system pathologies such as neurotrauma, stroke, infections, and neurodegenerative diseases like Alzheimer\'s and Huntington\'s disease, astrocytes undergo significant morphological, molecular, and metabolic changes. Reactive astrocytes upregulate glycolysis and fatty acid oxidation to meet increased energy demands, which can be protective in acute settings but may exacerbate chronic inflammation and disease progression. This review emphasizes the need for advanced molecular, genetic, and physiological tools to further understand astrocyte heterogeneity and their metabolic reprogramming in disease states.

Cardiovascular disease remains a leading cause of death worldwide despite important advances in modern medical and surgical therapies. As human adult cardiomyocytes have limited regenerative ability, cardiomyocytes lost after myocardial infarction are replaced by fibrotic scar tissue, leading to cardiac dysfunction and heart failure. To replace lost cardiomyocytes, a promising approach is direct cardiac reprogramming, in which cardiac fibroblasts are transdifferentiated into induced cardiomyocyte-like cells (iCMs). Here we review cardiac reprogramming cocktails (including transcription factors, microRNAs and small molecules) that mediate iCM generation. We also highlight mechanistic studies exploring the barriers to and facilitators of this process. We then review recent progress in iCM reprogramming, with a focus on single-cell \'-omics\' research. Finally, we discuss obstacles to clinical application.

Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

Induced pluripotent stem cells (iPSCs) that are generated from adult somatic cells are induced to express genes that make them pluripotent through reprogramming techniques. With their unlimited proliferative capacity and multifaceted differentiation potential and circumventing the ethical problems encountered in the application of embryonic stem cells (ESC), iPSCs have a broad application in the fields of cell therapy, drug screening, and disease models and may open up new possibilities for regenerative medicine to treat diseases in the future. In this review, we begin with different reprogramming cell technologies to obtain iPSCs, including biotechnological, chemical, and physical modulation techniques, and present their respective strengths, and limitations, as well as the recent progress of research. Secondly, we review recent research advances in iPSC reprogramming-based regenerative therapies. iPSCs are now widely used to study various clinical diseases of hair follicle defects, myocardial infarction, neurological disorders, liver diseases, and spinal cord injuries. This review focuses on the translational clinical research around iPSCs as well as their potential for growth in the medical field. Finally, we summarize the overall review and look at the potential future of iPSCs in the field of cell therapy as well as tissue regeneration engineering and possible problems. We believe that the advancing iPSC research will help drive long-awaited breakthroughs in cellular therapy.

OBJECTIVE: To establish a methodological system for reprogramming rat embryonic fibroblasts (REF) into chemically induced neurons (ciNCs) via small molecule compounds to provide safe and effective donor cells for treatment of neurodegenerative diseases.
METHODS: Based on the method established by PEI Gang\'s research group to directly reprogram human fibroblasts into neurons, the induction medium and maturation medium was optimized by replacing the coating solution, mitigating oxidative stress injury, adding neurogenic protective factors, adjusting the concentration of trichothecenes, performing small-molecule removal experiments, and carrying out immunofluorescence and Western blotting on cells at different stages of induction to validate the effect of induction.
RESULTS: When the original protocol was used for induction, the cell survival rate was (34.24±2.77)%. After replacing the coating solution gelatin with matrigel, the cell survival rate increased to (45.41±4.27)%; after adding melatonin, the cell survival rate increased to (67.95±5.61)% and (23.43±1.42)% were transformed into neural-like cells; after adding the small molecule P7C3-A20, the cell survival rate was further increased to (76.27±1.41)%, and (39.72±4.75)% of the cells were transformed into neural-like cells. When the concentration of trichothecene was increased to 30 μmol/L, the proportion of neural-like cells reached (55.79±1.90)%; after the removal of SP600125, (86.96±2.15)% of the cells survived, and the rate of neural-like cell production increased to (63.43±1.60)%. With the optimized protocol, REF could be successfully induced into ciNC through the neural precursor cell stage, in which the neural precursor cells were able to highly express the neural precursor cell markers SRY-related HMG-box gene 2 (Sox2) and paired box 6 (Pax6) as well as neuron-specific marker tubulin 1 (Tuj1), while the expression of fiber-associated protein vimentin was reduced. After two weeks of induction of neural precursor cells in a maturation medium, most cells displayed neuronal-like cell morphology. The induced ciNCs were able to highly express the mature neuronal surface markers Tuj1 and microtubule-associated protein 2 (MAP2), while the expression of vimentin was reduced.
CONCLUSIONS: The small molecule combinations optimized in this study can reprogram REF to ciNCs under normoxic conditions.
目的: 建立通过小分子化合物将大鼠胚胎成纤维细胞（REF）重编程为化学诱导神经元（ciNC）的方法体系，为细胞移植治疗神经退行性疾病提供安全有效的供体细胞。方法: 以裴钢研究团队建立的人成纤维细胞直接重编程为神经元的方法为基础，通过更换包被液、缓解氧化应激损伤、添加神经源性保护因子、调整毛喉素浓度和小分子去除实验对诱导培养基和成熟培养基进行优化，并通过免疫荧光法和蛋白质印迹法验证不同诱导阶段细胞的相关蛋白质。结果: 以原方案进行诱导时，细胞存活率仅（34.24±2.77）%。包被液更换为基质胶后，细胞存活率上升到（45.41±4.27）%；添加褪黑素后细胞存活率提高至（67.95±5.61）%，（23.43±1.42）%的细胞转变为神经样细胞；添加小分子P7C3-A20后细胞存活率进一步提升至（76.27±1.41）%，（39.72±4.75）%的细胞转变为神经样细胞；毛喉素浓度提升至30 μmol/L时，神经样细胞比例达到（55.79±1.90）%；去除SP600125后，（86.96±2.15）%细胞存活，神经样细胞生成率提高至（63.43±1.60）%。以优化后的方案诱导，可经过神经前体细胞将REF诱导为ciNC。其中，神经前体细胞能够高表达神经前体细胞标志物SRY-box转录因子2、配对盒6以及神经元特异性标志物Ⅲ类β-微管蛋白，而成纤维相关蛋白波形蛋白表达量减少。神经前体细胞在成熟培养基中诱导两周后，可见大部分细胞呈神经样细胞形态，诱导后的ciNC高表达Ⅲ类β-微管蛋白和微管相关蛋白2，而成纤维相关蛋白波形蛋白表达减少。结论: 优化后的小分子组合在常氧条件下能将REF重编程为ciNC。.

Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.

The tendency for cell fate to be robust to most perturbations, yet sensitive to certain perturbations raises intriguing questions about the existence of a key path within the underlying molecular network that critically determines distinct cell fates. Reprogramming and trans-differentiation clearly show examples of cell fate change by regulating only a few or even a single molecular switch. However, it is still unknown how to identify such a switch, called a master regulator, and how cell fate is determined by its regulation. Here, we present CAESAR, a computational framework that can systematically identify master regulators and unravel the resulting canalizing kernel, a key substructure of interconnected feedbacks that is critical for cell fate determination. We demonstrate that CAESAR can successfully predict reprogramming factors for de-differentiation into mouse embryonic stem cells and trans-differentiation of hematopoietic stem cells, while unveiling the underlying essential mechanism through the canalizing kernel. CAESAR provides a system-level understanding of how complex molecular networks determine cell fates.

Macrophages play crucial roles in the innate immune response, exhibiting context-dependent behaviors. Within the tumor microenvironment, macrophages exist as tumor-associated or M2-like macrophages, presenting reprogramming challenges. In this study, we develop a peptide hydrogel that is able to polarize M0 macrophages into pro-inflammatory M1 macrophages through the activation of NF-κB signaling pathways. Importantly, this system is also found to be capable of reprogramming M2 macrophages into pro-inflammatory M1-like macrophages by activating CD206 receptors. The nanofibrous hydrogel self-assembles from a short peptide that contains an innate defense regulator peptide and a self-assembly promoting motif, presenting densely arrayed regulators that multivalently engage with macrophage membrane receptors to not only polarize M0 macrophages but also repolarize M2 macrophages into M1-like macrophages. Overall, this work offers a promising strategy for reprogramming macrophages, holding the potential to enhance immunotherapy by remodeling immune-resistant microenvironments.