撰文丨王聪 编辑丨王多鱼 排版丨水成文 衰老 会损害 人类脂肪来源干细胞 （ human adipose-derived stem cell， hASC ） 的再生能力和分化潜能，但其功能衰退的潜在机制，目前仍不清楚。 2026 年 1 月 20 日， 空军军医大学 胡大海 、 申亮亮 、 宋保强 等人在 Cell Discovery 期刊发表了题为： IGF2BP3-dependent glutamine/BCAA metabolic rewiring rejuvenates aged human adipose-derived stem cells for enhanced tissue regeneration 的研究论文。 该研究表明， IGF2BP3 依赖的谷氨酰胺/支链氨基酸代谢重编程，使衰老的 人类脂肪来源干细胞 （hASC） 恢复年轻活力，以增强组织再生。 https://www.nature.com/articles/s41421-025-00860-7 设置 星标 ，不错过精彩推文 在这项新研究中，研究团队通过系统的功能检测和体内实验，首先证实了 人类脂肪来源干细胞 （hASC） 的自我更 ...

Core Viewpoint - Obesity is a significant global public health crisis linked to various chronic diseases, characterized by persistent low-grade inflammation that exacerbates disease progression [6][7]. Group 1: Research Findings - A study published in Science reveals that obesity reshapes macrophage nucleotide metabolism, leading to hyperactivation of the NLRP3 inflammasome and uncontrolled inflammation, accelerating disease progression [3][4]. - The study identifies SAMHD1 as an intrinsic inhibitor in macrophages that can suppress NLRP3 inflammasome activation across species from fish to humans [3]. Group 2: Mechanisms of Inflammation - The NLRP3 inflammasome acts as an "alarm" in the immune system, activated by tissue damage or stress, producing pro-inflammatory cytokines like IL-1β, which, in obesity, disrupt insulin signaling and accelerate metabolic diseases [9]. - Obese individuals exhibit an increased amount of oxidized mitochondrial DNA (ox-mtDNA) in their immune cells, which activates the NLRP3 inflammasome [11][12]. Group 3: Role of SAMHD1 - SAMHD1 is crucial for maintaining nucleotide balance in cells, and obesity leads to its phosphorylation and functional impairment, resulting in excessive NLRP3 inflammasome activation [14]. - The absence of functional SAMHD1 in animal models leads to NLRP3 hyperactivation, indicating its role as a regulatory mechanism against inflammation [14]. Group 4: Metabolic Reprogramming - Obesity alters the metabolic pathways in immune cells, allowing excess dNTPs to enter mitochondria via nucleotide transport proteins, bypassing normal synthesis pathways and leading to uncontrolled mtDNA synthesis [16]. - Blocking dNTP transport into mitochondria can reverse obesity-related inflammation, suggesting a potential therapeutic direction [16]. Group 5: Clinical Implications - Mice lacking SAMHD1 exhibit typical metabolic abnormalities after a high-fat diet, and blocking dNTP transport alleviates these symptoms [18]. - The study's findings indicate that targeting mitochondrial dNTP transport could lead to new therapies for chronic inflammation and metabolic diseases associated with obesity, offering a more precise approach than traditional immune response suppression methods [18].

Core Insights - The article discusses the anticipated hot research areas for the National Natural Science Foundation of China (NSFC) funding in 2026, emphasizing the importance of understanding these trends for project design [4][5]. Group 1: Core Mechanisms - Key focus areas include immune regulation (macrophage polarization, neutrophil function, T-cell exhaustion), mitochondrial function and homeostasis, novel cell death mechanisms (ferroptosis, pyroptosis), metabolic reprogramming (glycolysis, lactylation), and post-translational modifications of proteins (ubiquitination, SUMOylation) [4]. Group 2: Frontier Interdisciplinary Areas - Emerging fields highlighted are epitranscriptomics (RNA modifications like m6A, m7G), intercellular communication (exosomes), host-microbiome interactions (gut microbiota), and stem cells with regenerative medicine [5]. Group 3: Key Technologies - Important technological advancements include single-cell and spatial multi-omics, organoids and disease models, and AI/machine learning-driven target discovery and data analysis [5]. Group 4: Research Case Studies - The article presents several research cases that exemplify how researchers are engaging with these hot topics, including: - Neutrophils and their role in thrombosis, published in the European Heart Journal [12]. - Immune evasion mechanisms in tumors, published in Cell [13]. - Gut microbiota's role in Crohn's disease, published in Gut [14]. - Glycolysis and its implications in cancer, published in Signal Transduction and Targeted Therapy [14]. - Development of organoids for bone repair, published in Advanced Materials [14].

Core Viewpoint - The study published in Cell highlights that chronic metabolic stress from high-fat diets not only leads to fatty liver but also induces profound changes in liver stem cells, which can promote tumorigenesis [1][2]. Group 1: Research Findings - Chronic stress forces liver cells to choose between survival and maintaining organ function, leading to early adaptive changes that can "pre-program" future tumor development [3][4]. - The research utilized a high-fat diet mouse model to simulate human metabolic dysfunction related to fatty liver disease, tracking changes in liver cells through multi-omics analysis [5]. - Chronic metabolic stress activates two core programs in liver cells: an upregulation program that promotes cell survival and regeneration while downregulating liver-specific functions, leading to decreased liver function [6]. Group 2: Key Mechanisms - The decline of the ketogenesis rate-limiting enzyme HMGCS2 is crucial, as its knockout in liver cells under high-fat diet stress exacerbates stress responses and significantly increases tumor incidence [8]. - The transcription factors SOX4 and RELB play a central role in promoting liver cell dedifferentiation and proliferation under stress, with high expression levels in patients with metabolic dysfunction-associated fatty liver disease (MASLD) indicating poor prognosis [10]. Group 3: Clinical Implications - The study reveals a "memory effect" of chronic stress and suggests monitoring the expression of genes like HMGCS2 and SOX4 as early risk markers for liver cancer [14]. - Targeting metabolic pathways, such as ketogenesis, or transcription factors like SOX4 may block precancerous states, providing potential intervention strategies [15]. - Overall, the adaptation of the liver to chronic metabolic stress enhances short-term cell survival but sacrifices long-term liver function, emphasizing the importance of healthy diets and metabolic stress control in preventing liver cancer [17].

Core Insights - The article discusses a new research study that addresses the impaired cellular behavior during the healing process in the elderly, focusing on the role of pro-inflammatory macrophages and aging stem cells in tissue regeneration [2][6]. Group 1: Research Findings - A research team from Zhejiang University and affiliated hospitals developed a spatiotemporal-adaptive nanotherapeutic system that utilizes a glucose-modified mixed membrane delivery strategy to precisely regulate metabolic reprogramming [3][6]. - The system employs NAD+ loaded ZIF-8 nanoparticles (NZM) to target pro-inflammatory macrophages during the inflammatory phase, triggering the release of NAD+ and inducing an anti-inflammatory transition [6]. - In the repair phase, the system restores NAD+ levels in aging stem cells, promoting tissue regeneration [6]. Group 2: Implications and Applications - The study demonstrates that the NAD+ can reprogram dysfunctional cells, effectively reshaping the multicellular regenerative microenvironment [6]. - The proposed strategy has shown to restore bone regeneration capabilities in osteoporotic mice and accelerate skin wound healing [6][7]. - This research connects cellular metabolism, nanomedicine, and regenerative therapy, offering a promising and translatable new strategy for precise clinical interventions [7].

Core Viewpoint - The research identifies a metabolic vulnerability in glioblastoma, revealing that the tumor relies on "stealing" serine from its environment for rapid growth, which can be targeted for treatment [4][8]. Group 1: Research Findings - Glioblastoma is the most common and aggressive primary malignant brain tumor in adults, with standard treatments including surgery, radiotherapy, and temozolomide chemotherapy, but it often recurs, leading to a high mortality rate within 1-2 years post-diagnosis [3]. - The study published in Nature highlights that glioblastoma tumors can utilize serine from their surroundings instead of synthesizing it, presenting a critical metabolic weakness [4][8]. - By feeding glioblastoma mouse models a diet lacking serine, researchers observed a slowdown in tumor growth and spread, extending survival time [4][8]. Group 2: Metabolic Mechanism - The research team analyzed samples from eight glioblastoma patients and found that tumors utilize glucose from the environment to synthesize essential components like DNA, facilitating aggressive growth [6][7]. - In healthy brain tissue, glucose is metabolized for the tricarboxylic acid (TCA) cycle and converted into serine, while glioblastoma bypasses serine synthesis by "stealing" it, allowing glucose to be redirected for synthesizing nucleotides necessary for cancer cell proliferation [7][8]. Group 3: Clinical Implications - The study suggests that the reliance on serine presents a targetable metabolic vulnerability, and the team plans to conduct clinical trials on a serine-restricted diet for patients, which, while not curative, could provide additional time for some patients [8].

Core Viewpoint - The study highlights the role of C19orf12 as a mitochondrial metabolic regulator in non-small cell lung cancer (NSCLC), indicating that elevated expression levels may serve as a biomarker for improved response to metformin treatment [10]. Group 1: Research Findings - C19orf12 is highly expressed in NSCLC and is associated with poor prognosis [7]. - C19orf12 regulates mitochondrial function and drives glucose metabolic reprogramming [7]. - C19orf12 interacts with LRPPRC protein, downregulating the expression of mitochondrial electron transport chain complexes I and IV [7]. - High levels of C19orf12 inhibit mitochondrial respiration and reduce glucose flux through the tricarboxylic acid (TCA) cycle [5][6]. Group 2: Implications for Treatment - C19orf12 enhances the sensitivity of NSCLC cells to the antitumor effects of metformin [6]. - The study suggests that C19orf12 expression levels could predict the response to metformin treatment in NSCLC patients [10].

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [4][12]. Group 1: Mechanism of Drug Resistance - RIOK1 phase separation mediates the formation of stress granules under TKI treatment stress, recruiting IGF2BP1 and G3BP1 to form dynamic stress granules [11]. - Stress granules selectively encapsulate PTEN mRNA, inhibiting its translation into PTEN protein, leading to the inactivation of the PTEN/PI3K/AKT pathway [11]. - The loss of PTEN activates the pentose phosphate pathway (PPP), increasing NADPH production and antioxidant capacity, helping cancer cells eliminate TKI-induced reactive oxygen species (ROS) [11]. Group 2: Key Findings and Clinical Relevance - The NRF2-RIOK1 regulatory axis is activated by oxidative stress (e.g., TKI treatment), upregulating RIOK1 expression and enhancing cancer cell adaptability through a positive feedback loop [11]. - The study establishes a causal chain linking stress granules, metabolic reprogramming, and TKI treatment resistance in HCC [12]. Group 3: Research Significance and Translational Directions - Targeting RIOK1 phase separation may disrupt the cancer cell's "stress buffering system," providing a new direction to improve TKI efficacy [12]. - Combination therapy of TKI and Chidamide may synergistically enhance anti-tumor effects [13]. - RIOK1 expression levels or the dynamics of stress granules could serve as predictive biomarkers for TKI efficacy, guiding personalized treatment [13].

Core Viewpoint - The study identifies AKR1B1 as a key regulatory enzyme in metabolic reprogramming and a potential biomarker and therapeutic target for hepatocellular carcinoma (HCC), suggesting that targeting AKR1B1 can reverse systemic therapy resistance in HCC [3][7]. Group 1: Research Findings - HCC is a major subtype of liver cancer and a leading cause of cancer-related deaths globally, with high incidence and mortality rates [2]. - The research team established HCC cell lines with multidrug resistance characteristics, observing enhanced metabolic activity in these cells [5]. - Multi-omics analysis revealed that glucose-lipid and glutathione metabolic pathways are overactive, playing critical roles in supporting tumor cell proliferation and survival [5]. Group 2: Mechanism of Resistance - The study constructed a metabolic reprogramming map for resistant HCC cells, identifying AKR1B1 as a key regulatory factor that maintains resistance by modulating energy metabolism and enhancing stress tolerance [5]. - The expression level of AKR1B1 is closely related to drug resistance and poor prognosis in HCC patients, highlighting its predictive value [5]. Group 3: Therapeutic Implications - The combination of Epalrestat, a clinically approved AKR1B1 inhibitor, with standard therapy (Lenvatinib) significantly alleviated resistance in HCC [7]. - The findings provide new insights into the mechanisms of resistance in HCC and lay the theoretical foundation for developing new predictive biomarkers and therapeutic strategies to overcome resistance [7].

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [2][3][6]. Group 1: Research Findings - RIOK1 is highly expressed in HCC and is associated with poor prognosis, activated by NRF2 under various stress conditions [6]. - RIOK1 facilitates liquid-liquid phase separation (LLPS) by incorporating IGF2BP1 and G3BP1 into stress granules, which sequester PTEN mRNA, reducing its translation [6]. - This process activates the pentose phosphate pathway, helping cells cope with stress and protecting them from the effects of tyrosine kinase inhibitors (TKIs) [6]. Group 2: Implications for Treatment - The small molecule Chidamide, a selective histone deacetylase inhibitor, can downregulate RIOK1 and enhance the efficacy of TKIs [6]. - RIOK1-positive stress granules were found in tumors of HCC patients resistant to Donafenib, indicating a potential target for overcoming drug resistance [6][7]. Group 3: Broader Context - The findings connect the dynamic changes of stress granules and metabolic reprogramming to the progression of HCC, suggesting potential strategies to improve TKI efficacy [7]. - A related article in Nature Cancer discusses how cancer cells form stress granules to adapt to stress and survive, highlighting the role of RIOK1-mediated phase separation in drug resistance [8].