Auxin regulates many aspects of plant growth and development, featuring polar auxin transport mediated by auxin efflux and influx carriers. AUX1 is the prominent auxin importer that actively takes up natural and synthetic auxins. However, the precise mechanisms by which AUX1 recognizes and transports auxin remain elusive. Here, we describe the cryo-electron microscopy structures of Arabidopsis thaliana AUX1 in apo and auxin-bound forms, revealing the structural basis for auxin recognition. AUX1 assumes the LeuT-like fold in an inward conformation. The auxin analogue 2,4-D is recognized by polar residues in the middle of AUX1. We identify a putative cation site in AUX1, which plays a role in stabilizing the inward-facing conformation. His249 undergoes a large conformational shift, and mutation of it completely abolished transport activity, suggesting a crucial role of His249 in AUX1 gating. Together, this study provides a structural foundation for a deeper comprehension of auxin influx by AUX1-like carriers.
Xiaojiao Guo, Lei Gao, Shiwei Li, Jing Gao, Yuanyuan Wang, Jing Lv, Jiayi Wei, Jing Yang, Han Ke, Qi Ding, Jun Yang, Fusheng Guo, Haowen Zhang, Xiaoguang Lei & Le Kang
Nature (2025). DOI： 10.1038/s41586-025-09110-y
Aggregation pheromone, 4-vinylanisole (4VA), is specifically released by gregarious migratory locusts, and is crucial in forming locust swarms that cause destructive plagues1. Control of locust plagues relies heavily on the extensive application of chemical pesticides, which has led to severe environmental and health issues2. As pheromones are primary mediators of insect communication and behaviour3, exploring their biosynthesis can provide important cues to develop innovative behavioural regulators, potentially reducing the reliance on chemical pesticides. Here we resolve the biosynthesis of 4VA and behavioural responses of locusts when enzymes in the 4VA biosynthetic pathway are manipulated. The process initiates with phenylalanine derived from food plants and proceeds through three precursors: cinnamic acid, p-hydroxycinnamic acid and 4-vinylphenol (4VP). Notably, the conversion from 4VP to 4VA through methylation is unique to gregarious locusts. This step is catalysed by two crucial methyltransferases, 4VPMT1 and 4VPMT2. Guided by the X-ray co-crystal structure of 4VPMT2 bound with 4VP and S-adenosyl-L-methionine, we developed 4-nitrophenol as a substrate surrogate. We identified several chemicals that can block 4VA production by inhibiting the enzymatic activities of 4VPMT proteins, thereby suppressing locust aggregative behaviour. The findings uncover the chemical logic behind 4VA biosynthesis and pinpoint two crucial enzymes as novel targets for locust swarm management.
Jun Yang, Yuling Zhu, Yunxi Han, Han Ke, Jing Zhang, Ming-Wei Wang, Xiaoguang Lei*
ACS Catal. 2025, 15, 11664–11672
Trichothecenes, particularly T-2 toxin (T-2), pose significant threats to food safety as well as to both animal and human health. Although Fhb7 and its variants have been utilized for deoxynivalenol degradation, no enzyme with efficient T-2 degradation activity has been reported. Herein, we generated five enzymes derived from Fhb7 that are capable of T-2 degradation via ancestral sequence reconstruction. Among these, N1, N2, and N4 exhibited superior catalytic activity toward T-2 compared to the parent enzyme Fhb7 and its variants. Structural analyses revealed that residue F27 provides a hydrophobic environment for accommodation of the unique 3-methylbutyryl group of T-2. In addition, the long insertion loop of N2 plays a key role in its improved substrate preference. Furthermore, all the ancestors displayed remarkable thermostability, with N2 and N4 displaying superior thermal tolerance (Tm values are 54 and 59 °C, respectively, and their half-life times are longer than 90 h), positioning them as a promising candidate for industrial applications. This work introduces a promising enzymatic approach for T-2 degradation and lays a foundation for developing robust biocatalysts for the environmental and industrial bioremediation of mycotoxins.
With the continuous elucidation of biosynthetic enzymes for natural products, the application of enzymes asunique biological resources in the total synthesis of natural products has become increasingly widespread, driving thechemoenzymatic strategy to emerge as a research hotspot in this field. The use of enzymes not only enhances theprecision and efficiency of natural product synthesis but also expands the boundaries of traditional chemical synthesis,promoting the in-depth development and utilization of natural product resources. Based on the research practices of ourgroup and representative work from other domestic groups over the past three years, this article systematicallysummarizes the three major application dimensions of enzyme-catalyzed reactions in natural product synthesis:providing new synthetic starting points, driving the construction of complex scaffolds, and facilitating precise late-stagemodifications. This provides a reference for the further application of enzyme resources in natural product synthesis.
Transcription factors (TFs) play essential roles in cancer and metabolic diseases, and targeting TFs with small molecules remains a significant challenge. The TF PU.1 is critical for maintaining leukemia initiation cells (LICs) “stemness” in acute T cell lymphoblastic leukemia (T-ALL) and is also a key regulator of fibroblast polarization and organ fibrosis. Herein we rationally designed and synthesized a variety of diamidines with rigid and AT-selective linkers as PU.1 inhibitors. The compound PKU0140 displayed the highest potency in reducing the expression of PU.1 target genes. Significantly, PKU0140 allosterically disrupted the PU.1-chromatin interaction by binding to the minor groove of DNA. In the Pten-null T-ALL mouse model, PKU0140, combined with rapamycin, could significantly decrease leukemic blasts and LICs, alleviate leukemia progression, and prolong the survival of mice. Furthermore, PKU0140 showed preventive and therapeutic effects on fibrotic lesions in various organs by inhibiting the activation of myofibroblasts. This work provides a new small-molecule PU.1 inhibitor with the potential for the treatment of T-ALL and organ fibrosis.
Plants employ immune receptors to perceive pathogen-associated molecular patterns (PAMPs) to trigger immune signaling. How plants impede pathogen progression following successful signal transduction, however, has remained largely elusive. Plants produce diverse secondary metabolites, called phytoalexins, in response to pathogen infections. Various phytoalexins show strong lineage specificity and are believed to act upon microbes by growth inhibition or toxicity. Whether any phytoalexins protect plants by targeting specialized virulence machinery of pathogens has not been well studied. For instance, numerous gram-negative bacterial pathogens employ the type III secretion system (T3SS), a multiprotein injectisome, to deliver virulence proteins into animal and plant host cells for pathogenesis. Immune-activated plants are known to possess activity that inhibits the bacterial T3SS, although the nature of this activity and underlying mechanism remain unknown. This immune-induced anti-T3SS activity serves as a model to investigate potential antivirulence phytoalexins in plants.
Junping Fan*, Wenjun Xie, Han Ke, Jing Zhang, Jin Wang, Haijun Wang, Nianxin Guo, Yingjie Bai, Xiaoguang Lei*
JACS Au 2025, https://doi.org/10.1021/jacsau.4c01188
The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
Recently, ligand-promoted Au(I)/Au(III)-catalyzed cross-coupling reactions with aryl iodides have garnered considerable attention. Here, we report the first visible-light-driven gold-catalyzed cross-couplings of challenging aryl bromides. In the presence of a (P, N)-gold(I) catalyst and an acridinium photocatalyst under blue LED irradiation, C–O coupling of aryl bromides with carboxylic acids was achieved, and soon it was found that this photoinduced gold-catalyzed cross-coupling of aryl bromides was appliable for other C–C, C–N, and C–S bond formation. Experimental and computational studies suggest that this visible-light-driven gold-catalyzed cross-couplings of aryl bromides involves two discrete photoinduced energy transfer (EnT) events: first, energy transfer (EnT) from a photosensitizer produces an excited-state gold(I) complex that allows the bottleneck oxidative addition of aryl bromides to form an aryl Au(III) complex and second, the reductive elimination of aryl-Au(III) complex to regenerate Au(I). Collectively, the new synergistic catalytic method developed here highlights the tremendous potential of photochemical gold catalysis via excited-state organogold complexes, as well as its potential to facilitate drug discovery due to the biocompatibility and mildness of the reaction conditions.
Yi Yang, Ling Jiao, Fusheng Guo, Yibin Sun, Hongyang Cui, Xiaoguang Lei, Jianying Hu, Yi Wan*
Environ. Sci. Technol. 2025, 59, 5, 2368–2377.
Metabolism-disrupting chemicals (MDCs) have attracted widespread attention due to their contributions to the prevalence of metabolic diseases worldwide. The farnesoid X receptor (FXR) is a typical lipid-sensing nuclear receptor and plays a crucial role in the development of metabolic diseases. However, few studies have examined the FXR activities of environmental samples and the corresponding MDCs. In this study, we found FXR-antagonistic activities in 93.6% of source water, surface water, and wastewater samples (n = 78) collected from the Yangtze River and Yellow River. An FXR protein-affinity guided nontargeted analysis was performed and identified 79 potential FXR-active pollutants in samples from these two rivers. Nine of these pollutants exhibited strong FXR-antagonistic activities (IC50: 2.39–141.9 μM), and 6 pollutants, including triphenyl phosphate (TPHP), 4,4′-sulfonylbis[2-(2-propenyl) phenol (TGSA), tonalid (AHTN), dichlorophen, etoxazole (ETX), and loratadine, were identified to be FXR antagonists for the first time. The total concentrations of the nine FXR-antagonistic pollutants were relatively high in the middle and downstream reaches of the Yellow River and the downstream reaches of the Yangtze River, and two pollutants (TGSA and ETX) have not previously been found in aquatic environments. A risk prioritization analysis revealed that TPHP, TGSA, and AHTN are priority pollutants with the potential to affect the FXR. Appropriate management of these priority pollutants would reduce the health risks of metabolic disruptions associated with exposure to these MDCs.
Signal Transduction and Targeted Therapy, 2024, 9, 338.
Erythropoiesis is a crucial process in hematopoiesis, yet it remains highly susceptible to disruption by various diseases, which significantly contribute to the global challenges of anemia and blood shortages. Current treatments like erythropoietin (EPO) or glucocorticoids often fall short, especially for hereditary anemias such as Diamond-Blackfan anemia (DBA). To uncover new erythropoiesis-stimulating agents, we devised a screening system using primary human hematopoietic stem and progenitor cells (HSPCs). We discovered that BRAF inhibitors (BRAFi), commonly used to treat BRAFV600E melanoma, can unexpectedly and effectively promote progenitor cell proliferation by temporarily delaying erythroid differentiation. Notably, these inhibitors exhibited pronounced efficacy even under cytokine-restricted conditions and in patient samples of DBA. Mechanistically, although these BRAFi inhibit the MAPK cascade in BRAFV600E mutant cells, they paradoxically act as amplifiers in wild-type BRAF cells, potently enhancing the cascade. Furthermore, we found that while the oncogenic BRAFV600E mutation disrupts hematopoiesis and erythropoiesis through AP-1 hyperactivation, BRAFi minimally impact HSPC self-renewal and differentiation. In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.
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Structural basis of auxin recognition and transport in plant influx carrier AUX1
Huiwen Chen1, Junping Fan1, Cheng Chi1, Jun Zhao, Di Wu, Xiaoguang Lei*, Xingwang Deng*, Daohua Jiang*
Molecular Plant, 2025.
doi.org/10.1016/j.molp.2025.06.015
Auxin regulates many aspects of plant growth and development, featuring polar auxin transport mediated by auxin efflux and influx carriers. AUX1 is the prominent auxin importer that actively takes up natural and synthetic auxins. However, the precise mechanisms by which AUX1 recognizes and transports auxin remain elusive. Here, we describe the cryo-electron microscopy structures of Arabidopsis thaliana AUX1 in apo and auxin-bound forms, revealing the structural basis for auxin recognition. AUX1 assumes the LeuT-like fold in an inward conformation. The auxin analogue 2,4-D is recognized by polar residues in the middle of AUX1. We identify a putative cation site in AUX1, which plays a role in stabilizing the inward-facing conformation. His249 undergoes a large conformational shift, and mutation of it completely abolished transport activity, suggesting a crucial role of His249 in AUX1 gating. Together, this study provides a structural foundation for a deeper comprehension of auxin influx by AUX1-like carriers.
Decoding 4-vinylanisole biosynthesis and pivotal enzymes in locusts
Xiaojiao Guo, Lei Gao, Shiwei Li, Jing Gao, Yuanyuan Wang, Jing Lv, Jiayi Wei, Jing Yang, Han Ke, Qi Ding, Jun Yang, Fusheng Guo, Haowen Zhang, Xiaoguang Lei & Le Kang
Nature (2025). DOI： 10.1038/s41586-025-09110-y
Aggregation pheromone, 4-vinylanisole (4VA), is specifically released by gregarious migratory locusts, and is crucial in forming locust swarms that cause destructive plagues1. Control of locust plagues relies heavily on the extensive application of chemical pesticides, which has led to severe environmental and health issues2. As pheromones are primary mediators of insect communication and behaviour3, exploring their biosynthesis can provide important cues to develop innovative behavioural regulators, potentially reducing the reliance on chemical pesticides. Here we resolve the biosynthesis of 4VA and behavioural responses of locusts when enzymes in the 4VA biosynthetic pathway are manipulated. The process initiates with phenylalanine derived from food plants and proceeds through three precursors: cinnamic acid, p-hydroxycinnamic acid and 4-vinylphenol (4VP). Notably, the conversion from 4VP to 4VA through methylation is unique to gregarious locusts. This step is catalysed by two crucial methyltransferases, 4VPMT1 and 4VPMT2. Guided by the X-ray co-crystal structure of 4VPMT2 bound with 4VP and S-adenosyl-L-methionine, we developed 4-nitrophenol as a substrate surrogate. We identified several chemicals that can block 4VA production by inhibiting the enzymatic activities of 4VPMT proteins, thereby suppressing locust aggregative behaviour. The findings uncover the chemical logic behind 4VA biosynthesis and pinpoint two crucial enzymes as novel targets for locust swarm management.
Developing Fhb7-Derived Enzymes with High Thermostability for Detoxification of T-2 Toxin through Ancestral Sequence Reconstruction
Jun Yang, Yuling Zhu, Yunxi Han, Han Ke, Jing Zhang, Ming-Wei Wang, Xiaoguang Lei*
ACS Catal. 2025, 15, 11664–11672
Trichothecenes, particularly T-2 toxin (T-2), pose significant threats to food safety as well as to both animal and human health. Although Fhb7 and its variants have been utilized for deoxynivalenol degradation, no enzyme with efficient T-2 degradation activity has been reported. Herein, we generated five enzymes derived from Fhb7 that are capable of T-2 degradation via ancestral sequence reconstruction. Among these, N1, N2, and N4 exhibited superior catalytic activity toward T-2 compared to the parent enzyme Fhb7 and its variants. Structural analyses revealed that residue F27 provides a hydrophobic environment for accommodation of the unique 3-methylbutyryl group of T-2. In addition, the long insertion loop of N2 plays a key role in its improved substrate preference. Furthermore, all the ancestors displayed remarkable thermostability, with N2 and N4 displaying superior thermal tolerance (Tm values are 54 and 59 °C, respectively, and their half-life times are longer than 90 h), positioning them as a promising candidate for industrial applications. This work introduces a promising enzymatic approach for T-2 degradation and lays a foundation for developing robust biocatalysts for the environmental and industrial bioremediation of mycotoxins.
The application of enzyme resources in the synthesis of natural products
Jin Wang, Haoran Dong, Xiaoguang Lei
SCIENTIA SINICA Chimica, 2025, 55(5): 1196-1202.
With the continuous elucidation of biosynthetic enzymes for natural products, the application of enzymes asunique biological resources in the total synthesis of natural products has become increasingly widespread, driving thechemoenzymatic strategy to emerge as a research hotspot in this field. The use of enzymes not only enhances theprecision and efficiency of natural product synthesis but also expands the boundaries of traditional chemical synthesis,promoting the in-depth development and utilization of natural product resources. Based on the research practices of ourgroup and representative work from other domestic groups over the past three years, this article systematicallysummarizes the three major application dimensions of enzyme-catalyzed reactions in natural product synthesis:providing new synthetic starting points, driving the construction of complex scaffolds, and facilitating precise late-stagemodifications. This provides a reference for the further application of enzyme resources in natural product synthesis.
Small-Molecule Inhibitors of Transcription Factor PU.1 for the Treatment of Acute T Cell Lymphoblastic Leukemia and Organ Fibrosis
Xin Wang, Liuzhen Zhang, Fusheng Guo, Ningning Yao, Zhenpeng Wu, Libing He, Dan Xu,Haichuan Zhu, Zhou Gong, Shuai Yang, Wenjun Xie, Yafen Wang, Liyun Zhang, Xiang Zhou10, Chun Tang,Rong Mu, Hong Wu* & Xiaoguang Lei*
CCS Chem. 2025, Just Published.
Transcription factors (TFs) play essential roles in cancer and metabolic diseases, and targeting TFs with small molecules remains a significant challenge. The TF PU.1 is critical for maintaining leukemia initiation cells (LICs) “stemness” in acute T cell lymphoblastic leukemia (T-ALL) and is also a key regulator of fibroblast polarization and organ fibrosis. Herein we rationally designed and synthesized a variety of diamidines with rigid and AT-selective linkers as PU.1 inhibitors. The compound PKU0140 displayed the highest potency in reducing the expression of PU.1 target genes. Significantly, PKU0140 allosterically disrupted the PU.1-chromatin interaction by binding to the minor groove of DNA. In the Pten-null T-ALL mouse model, PKU0140, combined with rapamycin, could significantly decrease leukemic blasts and LICs, alleviate leukemia progression, and prolong the survival of mice. Furthermore, PKU0140 showed preventive and therapeutic effects on fibrotic lesions in various organs by inhibiting the activation of myofibroblasts. This work provides a new small-molecule PU.1 inhibitor with the potential for the treatment of T-ALL and organ fibrosis.
A widespread plant defense compound disarms bacterial type III injectisome assembly
Pei Miao†, Haijun Wang†, Wei Wang†, Zhengdong Wang, Han Ke, Hangyuan Cheng, Jinjing Ni, Jingnan Liang, Yu-Feng Yao, Jizong Wang, Jian-Min Zhou*, Xiaoguang Lei*
Science, 2025, 387, eads0377.
Plants employ immune receptors to perceive pathogen-associated molecular patterns (PAMPs) to trigger immune signaling. How plants impede pathogen progression following successful signal transduction, however, has remained largely elusive. Plants produce diverse secondary metabolites, called phytoalexins, in response to pathogen infections. Various phytoalexins show strong lineage specificity and are believed to act upon microbes by growth inhibition or toxicity. Whether any phytoalexins protect plants by targeting specialized virulence machinery of pathogens has not been well studied. For instance, numerous gram-negative bacterial pathogens employ the type III secretion system (T3SS), a multiprotein injectisome, to deliver virulence proteins into animal and plant host cells for pathogenesis. Immune-activated plants are known to possess activity that inhibits the bacterial T3SS, although the nature of this activity and underlying mechanism remain unknown. This immune-induced anti-T3SS activity serves as a model to investigate potential antivirulence phytoalexins in plants.
Structural Basis for Inhibition of Urate Reabsorption in URAT1
Junping Fan*, Wenjun Xie, Han Ke, Jing Zhang, Jin Wang, Haijun Wang, Nianxin Guo, Yingjie Bai, Xiaoguang Lei*
JACS Au 2025,
https://doi.org/10.1021/jacsau.4c01188
The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
Photosensitized Gold-Catalyzed Cross-Couplings of Aryl Bromides
Jiawen Wu, Fusheng Guo, Chenju Yi, Rongjie Yang, Xiaoguang Lei, Zhonghua Xia*
J. Am. Chem. Soc. 2025, 147, 7, 5839–5850.
Recently, ligand-promoted Au(I)/Au(III)-catalyzed cross-coupling reactions with aryl iodides have garnered considerable attention. Here, we report the first visible-light-driven gold-catalyzed cross-couplings of challenging aryl bromides. In the presence of a (P, N)-gold(I) catalyst and an acridinium photocatalyst under blue LED irradiation, C–O coupling of aryl bromides with carboxylic acids was achieved, and soon it was found that this photoinduced gold-catalyzed cross-coupling of aryl bromides was appliable for other C–C, C–N, and C–S bond formation. Experimental and computational studies suggest that this visible-light-driven gold-catalyzed cross-couplings of aryl bromides involves two discrete photoinduced energy transfer (EnT) events: first, energy transfer (EnT) from a photosensitizer produces an excited-state gold(I) complex that allows the bottleneck oxidative addition of aryl bromides to form an aryl Au(III) complex and second, the reductive elimination of aryl-Au(III) complex to regenerate Au(I). Collectively, the new synergistic catalytic method developed here highlights the tremendous potential of photochemical gold catalysis via excited-state organogold complexes, as well as its potential to facilitate drug discovery due to the biocompatibility and mildness of the reaction conditions.
Protein-Affinity Guided Nontargeted Analysis Reveals the Widespread FXR-Antagonistic Pollutants in Surface Water and Source Water Along the Yangtze River and Yellow River
Yi Yang, Ling Jiao, Fusheng Guo, Yibin Sun, Hongyang Cui, Xiaoguang Lei, Jianying Hu, Yi Wan*
Environ. Sci. Technol. 2025, 59, 5, 2368–2377.
Metabolism-disrupting chemicals (MDCs) have attracted widespread attention due to their contributions to the prevalence of metabolic diseases worldwide. The farnesoid X receptor (FXR) is a typical lipid-sensing nuclear receptor and plays a crucial role in the development of metabolic diseases. However, few studies have examined the FXR activities of environmental samples and the corresponding MDCs. In this study, we found FXR-antagonistic activities in 93.6% of source water, surface water, and wastewater samples (n = 78) collected from the Yangtze River and Yellow River. An FXR protein-affinity guided nontargeted analysis was performed and identified 79 potential FXR-active pollutants in samples from these two rivers. Nine of these pollutants exhibited strong FXR-antagonistic activities (IC50: 2.39–141.9 μM), and 6 pollutants, including triphenyl phosphate (TPHP), 4,4′-sulfonylbis[2-(2-propenyl) phenol (TGSA), tonalid (AHTN), dichlorophen, etoxazole (ETX), and loratadine, were identified to be FXR antagonists for the first time. The total concentrations of the nine FXR-antagonistic pollutants were relatively high in the middle and downstream reaches of the Yellow River and the downstream reaches of the Yangtze River, and two pollutants (TGSA and ETX) have not previously been found in aquatic environments. A risk prioritization analysis revealed that TPHP, TGSA, and AHTN are priority pollutants with the potential to affect the FXR. Appropriate management of these priority pollutants would reduce the health risks of metabolic disruptions associated with exposure to these MDCs.
BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling
Shunkang Wu, Yuelin Deng, Haobo Sun, Xuewen Liu, Shuo Zhou, Hanxi Zhao, Huan Li, Fusheng Guo, Qiuyu Yue, Fan Wu, … Xiao-Jun Huang, Xiaoguang Lei, Xiangmin Tong, Xiaofei Gao & Hsiang-Ying Lee
Signal Transduction and Targeted Therapy, 2024, 9, 338.
Erythropoiesis is a crucial process in hematopoiesis, yet it remains highly susceptible to disruption by various diseases, which significantly contribute to the global challenges of anemia and blood shortages. Current treatments like erythropoietin (EPO) or glucocorticoids often fall short, especially for hereditary anemias such as Diamond-Blackfan anemia (DBA). To uncover new erythropoiesis-stimulating agents, we devised a screening system using primary human hematopoietic stem and progenitor cells (HSPCs). We discovered that BRAF inhibitors (BRAFi), commonly used to treat BRAFV600E melanoma, can unexpectedly and effectively promote progenitor cell proliferation by temporarily delaying erythroid differentiation. Notably, these inhibitors exhibited pronounced efficacy even under cytokine-restricted conditions and in patient samples of DBA. Mechanistically, although these BRAFi inhibit the MAPK cascade in BRAFV600E mutant cells, they paradoxically act as amplifiers in wild-type BRAF cells, potently enhancing the cascade. Furthermore, we found that while the oncogenic BRAFV600E mutation disrupts hematopoiesis and erythropoiesis through AP-1 hyperactivation, BRAFi minimally impact HSPC self-renewal and differentiation. In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.