Cancer cell-autonomous cGAS-STING response confers drug resistance.

The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained. Blockade of stimulator of interferon genes (STING) signaling delayed and overcame resistance in models in vitro and in vivo. This finding uncovers an alternative face of cGAS-STING signaling other than the well-reported modulation of microenvironmental immune cells. It also implies a caution for the combination of STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.

Short-term cultivation limiting soil aggregate stability and macronutrient accumulation associated with glomalin-related soil protein in Eucalyptus urophylla × Eucalyptus grandis plantations.

The relationship between glomalin-related soil protein (GRSP) and soil aggregation has been a hot topic of research for its close link to soil stability and quality. However, the short-term cultivation of Eucalyptus poses serious threats to soil stability and nutrient stocks, and the effects of GRSP on soil aggregate stability and macronutrient accumulation remain unclear. The aim is to clarify the potential mechanisms affecting soil aggregate stability and macronutrient accumulation in short-term Eucalyptus plantations. Five Eucalyptus urophylla × Eucalyptus grandis plantations with different cultivation periods (1-5 years) in this study were investigated, and a native evergreen broadleaf forest (0 year) was selected as control. The mean weight diameter index increased in the first 3 years and then significantly decreased during 5 years cultivation of Eucalyptus. Soil organic carbon (SOC) and total nitrogen also decreased after planting Eucalyptus for 3 years, but variation in total phosphorus was not obvious. The relative abundance of Glomeraceae and Claroideoglomeraceae decreased in the 5-year-old Eucalyptus plantations and was positively correlated with GRSP content. In pathway modeling, nutrient-acquisition enzyme activities positively affected GRSP and macronutrient content. Total GRSP (T-GRSP) had higher total effects than easily extractable GRSP on soil aggregate stability, and positively correlated with SOC in macroaggregates. Both T-GRSP and SOC had positive and direct effects on soil aggregate stability. Variance partitioning analysis further explained the contribution of GRSP and SOC to aggregate stability, particularly in >2 and 2-0.25 mm macroaggregates. Our results suggested that GRSP was directly associated with SOC content and soil aggregate stability, and was a potential key factor affecting soil aggregate stability in Eucalyptus plantations. Improving T-GRSP and SOC are efficient approaches for preventing the gradual deterioration of soil aggregate stability. Short-term cultivation should be carefully used in Eucalyptus plantations, and a new cultivation period is needed.

Comparison of Indirect and Direct Approaches to Identifying an Unfaithful Partner.

Infidelity has been operationalized inconsistently across studies, and measurement approaches have been employed that are not ideally suited for addressing the stigmatized and subjective nature of infidelity, thereby limiting the conclusions that can be drawn from this body of literature. In 2016, Thompson and O'Sullivan took a step toward addressing these shortcomings by implementing an indirect measurement approach. We extend their findings using a sample of 465 married and divorced individuals via MTurk. Substantially more participants reported having engaged in infidelity via the indirect approach than the direct approach, and results suggest that-in contrast to findings from direct questioning-similar percentages of men and women engage in self-defined infidelity. Implications for research and clinical practice are provided.

Soil qualities and change rules of Eucalyptus grandis × Eucalyptus urophylla plantation with different slash disposals.

Slash disposal changes soil quality by affecting soil properties and nutrient cycling, and the appropriate disposal approaches remain controversial. This work aimed to explore the impact of different slash disposal methods on soil qualities. For this purpose, a Eucalyptus grandis × Eucalyptus urophylla plantation that had been cultivated in 2002 and felled for the third time in 2016 was established in Hezhou City, China. Burning forest (BF, for moderate intensity fire) and no-burning forest (NF) were set in the plantation, and the native evergreen broadleaf forest near the plantation was used as the control (CK). Soils were sampled quarterly in 2017, and 27 indicators that represent soil physical, chemical, and biological properties were analyzed and compared through the analysis of the sustainability index (SI), which adopts five indices to calculate soil quality. The obtained data showed that the indicators of BF and NF, except for the total potassium content, were much lower than those of CK. The physical properties (Max-WHC, CWHC, Min-WHC, MMC, CPD, TPD) of NF were significantly better (29.07%, 30.98%, 29.61%, 52.08%, 21.89%, 19.76%) than those of BF, unlike the chemical properties of BF (SOM, TN, ACa, AFe, AMn, ACu, AZn) were significantly better than those of NF (45.61%, 81.33%, 12.78%, 23.18%, 96.13%, 144.30%, 114.04%). The enzymatic activities of NF (URE, APHO) were significantly better (43.33%, 156.58%)than those of BF, except the activities of INV (- 25.21%). Results of SI showed that the soil quality of CK was much better than that of BF, and NF the worst. But it exhibited the most unevenness of CK, followed by NF, and BF the best. The change rules of BF and NF were contrasting, and soil quality reached the same level after half a year. In summary, the soil qualities, either BF or CK, were not comparable to that of CK. BF increased the soil quality fleetly and transiently, and NF was sustainable for the eucalyptus plantation.

Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma.

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. SIGNIFICANCE: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.

Metabolomics analysis reveals Oct4 overexpression drives metabolic reprogramming and enhanced glycolysis and pentose phosphate pathway in lung adenocarcinoma cells.

Poor prognosis in the underlying mechanisms involved in lung adenocarcinoma and its treatment leads to low survival rates in patients. Emerging evidence indicates that cancer is primarily a metabolic disease and metabolic reprogramming is a well-established hallmark and driving force of cancer. Oct4, acting as an oncogene, is a major regulator of cell pluripotency. It can reprogram the differentiated cells into cancer stem cells (CSCs) and plays an oncogenic role when pathologically hijacked. However, data that Oct4, the genetic reprogramming factor, could induce metabolic reprogramming have been very limited, and the direct evidence in metabolic level whether Oct4 reprograms metabolome is lacking. In the present study, integrated untargeted and targeted metabolomics analyses were utilized to investigate metabolic changes induced by Oct4 overexpression in lung adenocarcinoma cells. The results suggested that elevated expression levels of Oct4 drive metabolic reprogramming. Oct4 overexpression redirects glucose catabolism to glycolysis pathway and to the oxidative pentose phosphate pathway (PPP). This study identifies unique pathways that are candidate therapeutic targets for the treatment of lung adenocarcinoma. This study also aims to improve our understanding of the cancer-promoting activity of Oct4 and help identify novel diagnostic and therapeutic strategies for cancer treatment.

The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia.

Mutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates in vitro but displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted the in vivo growth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors.

Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer.

Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice. We demonstrated that aldo-keto reductase family 1 member B1 (AKR1B1) interacts with and activates signal transducer and activator of transcription 3 (STAT3) to up-regulate the cystine transporter solute carrier family 7 member 11 (SLC7A11). This leads to enhanced cystine uptake and flux to glutathione de novo synthesis, reactive oxygen species (ROS) scavenging, protection from cell death, and EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Suppression of AKR1B1 with selective inhibitors, including the clinically approved antidiabetic drug epalrestat, restored the sensitivity of resistant cell lines to EGFR TKIs and delayed resistance in lung cancer patient-derived xenograft mice. Our findings suggest a metabolic mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the third-generation inhibitor osimertinib.

Previous mode of delivery affects subsequent pregnancy outcomes: a Chinese birth register study.

BACKGROUND: With the comprehensive implementation of the second child policy in China, the proportion of multiparous women has increased dramatically in the past few years. As nearly half of them have a history of previous cesarean delivery, there is widespread concern regarding complications of their pregnancy. METHODS: The aim of this study was to evaluate the effect of the previous delivery mode on subsequent pregnancy outcomes in the real world based on data from a Chinese birth registry. Birth registry data from July 1, 2016 to June 30, 2017 among a Chinese population were collected and analyzed retrospectively. This study included 14 representative hospitals from 10 provinces of China. All delivery data were collected by an internet-based system using a birth registration platform. The study enrolled 36,355 multiparas. Information extracted for analysis included basic demographic characteristics, previous delivery mode, current delivery mode, major maternal complications, and neonatal outcomes. Pregnancy outcomes of women with previous cesarean delivery (PCS group, n=14,774) were compared with the outcomes of women with previous vaginal delivery (PVD group, n=21,581). RESULTS: There were statistically significant differences in the major pregnancy outcomes between the PCS group and the PVD group. The PCS group had a higher incidence of cesarean section (CS), placenta previa, postpartum hemorrhage, uterus rupture, hysterectomy, gestational diabetes, gestational hypertension, delivery before 37 weeks of gestation, low birth weight, and Apgar Score at 5 min ≤3. CONCLUSIONS: Women with previous cesarean delivery had poorer pregnancy outcomes than women with previous vaginal delivery. Avoiding unnecessary CS, especially in primiparas is essential to improving maternal and neonatal outcomes in later pregnancies.

Erratum: Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase: Erratum.

[This corrects the article DOI: 10.7150/thno.23177.].

Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma.

BACKGROUND: Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. METHODS: The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD). RESULTS: HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGD-induced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA. CONCLUSIONS: HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical application of HupA and other AChEIs for glaucoma patients should be further investigated.

Research Hotspots and Trend Exploration on the Clinical Translational Outcome of Simulation-Based Medical Education: A 10-Year Scientific Bibliometric Analysis From 2011 to 2021.

BACKGROUND: In recent decades, an increasing number of studies have focused on the clinical translational effect of simulation-based medical education (SBME). However, few scientific bibliometric studies have analyzed the research hotspots and publication trends. This study aimed to investigate research hotspots and future direction in the clinical translational outcome of SBME via bibliometrics. METHOD: Relevant publications on the clinical translational outcomes of SBME from 2011 to 2021 were identified and retrieved from the Web of Science Core Collection (WOSCC). Software including VOSviewer (1.6.17) and CiteSpace (5.8R3) and a platform (bibliometric.com) were employed to conduct bibliographic and visualized analysis on the literature. RESULTS: A total of 1,178 publications were enrolled. An increasing number of publications were observed in the past decades from 48 in 2011 to 175 in 2021. The United States accounted for the largest number of publications (488, 41.4%) and citations (10,432); the University of Toronto and Northwestern University were the leading institutions. Academic Medicine was the most productive journal concerning this field. McGaghie W C and Konge L were the most influential authors in this area. The hot topic of the translational outcome of SBME was divided into 3 stages, laboratory phase, individual skill improvement, and patient outcome involving both technical skills and non-technical skills. Translational research of comprehensive impact and collateral outcomes could be obtained in the future. CONCLUSION: From the overall trend of 10 years of research, we can see that the research is roughly divided into three phases, from laboratory stage, individual skill improvement to the patient outcomes, and comprehensive impacts such as skill retention and collateral effect as cost-effectiveness is a major trend of future research. More objective evaluation measurement should be designed to assess the diverse impact and further meta-analysis and randomized controlled trials are needed to provide more clinical evidence of SBME as translational science.

NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs. We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein. NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells. Furthermore, we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2, and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs. Thus, we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.

Development and validation of a rapid, robust and sensitive UPLC-QQQ-MS/MS method for simultaneous quantification of GSH metabolism in lung cancer cells.

Changes in cellular metabolism accompany tumor therapeutic resistance. Metabolite concentrations specifically reflect the cellular state. Glutathione (GSH) metabolism maintains the redox homeostasis while also confers therapeutic resistance to cancer cells. However, analytical methods for studying GSH metabolism rely on high-resolution-based untargeted metabolomics. Since the aim of untargeted metabolomics studies is covering as much metabolites as possible, these methods lack sensitivity for simultaneous analysis of intracellular GSH-related metabolites with different polarities and structures. In this study, based on cultured lung cancer cells, we described a rapid, robust and sensitive ultra-performance liquid chromatography-triple quadrupole tandem mass spectrographic method (UPLC-QQQ-MS/MS) to simultaneously quantify a repertoire of GSH-related metabolites, including GSH, GSSG, glycine, cysteine, glutamine, glutamate, cystine, γ-glutamyl-cysteine and cysteinyl-glycine. This method avoided the use of derivatization and/or ion-pairing reagents and was validated according to United States Food and Drug Administration (US FDA) criteria. The lower limit of quantification was determined to be 0.5-100 ng/mL with lower limits of detection at 0.14-10.07 ng/mL. The intra- and inter-day precision values for all the analytes were <15% CV, and the accuracy ranged from 85.4% to 114% at three levels of quality control. This method combined simple preparation with rapid analytical procedure (8 min), allowed for high-throughput analysis of GSH metabolism in basic and therapeutic treatment conditions within cultured cells. Our data showed a significant alteration of GSH metabolism in two independent resistant cells compared to sensitive cells. This method monitored the impact of molecularly targeted drugs on GSH metabolism within lung cancer cells and therefore helped identifying potential metabolic vulnerability for the therapeutic resistance in lung cancer.

A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.

Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.

Dysregulated Urinary Arginine Metabolism in Older Adults With Amnestic Mild Cognitive Impairment.

Background: Urine samples, which capture an individual's metabolic profile, are ideal for the exploration of non-invasive biomarkers to confirm the amnestic mild cognitive impairment (aMCI) status of patients vs. unimpaired ones. Objective: We aimed to detect differentially metabolized amino acids, which are important objectives in metabolomics, garnering particular attention in biomedical pathogenesis from the urine of aMCI patients, which may give clinicians the possibility to intervene with early treatments that curb Alzheimer's disease (AD). Methods: The study included 208 subjects, 98 of whom were aMCI patients, and 110 who were control subjects without dementia. Urine samples were taken from each participant and supernatant was obtained for analysis. The concentrations of amino acids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Urinary arginine levels in aMCI patients are obviously lower than in normal controls (q < 0.2 and p < 0.05). Meanwhile, aMCI patients had significant reduced urinary global arginine bioavailability ratio (GABR), and GABR in urine displayed a positive correlation with the score of CMMSE. Conclusion: Urinary dysregulated arginine metabolism that may serve as a helpful clinical diagnostic biomarker for aMCI in older adults.

UPLC-MS-based metabolomics reveals metabolic dysregulation in ALDH1A1-overexpressed lung adenocarcinoma cells.

INTRODUCTION: Specific oncogenotypes can produce distinct metabolic changes in cancer. Recently it is considered that metabolic reprograming contributes heavily to drug resistance. Aldehyde dehydrogenase 1A1 (ALDH1A1), is overexpressed in drug resistant lung adenocarcinomas and may be the cause of acquired drug resistance. However, how ALDH1A1 affects metabolic profiling in lung adenocarcinoma cells remains elusive. OBJECTIVE: We sought to investigate metabolic alterations induced by ALDH1A1 in lung adenocarcinoma in order to better understand the reprogramming and metabolic mechanism of resistance induced by ALDH1A1. METHODS: Metabolic alterations in lung adenocarcinoma HCC827-ALDH1A1 cells were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). HCC827-ALDH1A1 metabolic signatures were extracted by univariate and multivariate statistical analysis. Furthermore, metabolite enrichment analysis and pathway analysis were performed using MetaboAnalyst 4.0 software. RESULTS: Twenty-two metabolites were positively identified using authentic standards, including uridine monophosphate (UMP), uridine diphosphate (UDP), adenosine diphosphate (ADP), malic acid, malonyl-coenzyme A, nicotinamide adenine dinucleotide (NAD), coenzyme A and so on. Furthermore, metabolic pathway analysis revealed several dysregulated pathways in HCC827-ALDH1A1 cells, including nucleotide metabolism, urea cycle, tricarboxylic acid (TCA) cycle, and glycerol phospholipid metabolism etc. CONCLUSION: Lung cancer is the most frequent cause of cancer-related deaths worldwide. Nearly all patients eventually undergo disease progression due to acquired resistance. Mechanisms of biological acquired resistance need to be identified. Our study identified altered metabolites in HCC827-ALDH1A1 cells, enhancing our knowledge of lung adenocarcinoma metabolic alterations induced by ALDH1A1, creating a novel therapeutic pathway. These metabolic signatures of ALDH1A1 overexpression may shed light on molecular mechanisms in drug-resistant tumors, and on candidate drug targets. Furthermore, new molecular targets may provide the foundation for potential anticancer strategies for lung cancer therapy.

PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21.

In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we could monitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells.