Cell Reports
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2026
·Vol. 45
·期 3
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IF 7.7
Jiaqi Huang,Yuejue Wang,Fei Li,Nan Zhang,Guoxiong Tian,Dongyu Guo,Yanqi Guo,Zhengyuan Liu,Yinfang Wu,Xiaoping Li,Fei Xu,Zhongnan Qin,Ruixin Jia,Lingling Dong,Shenwei Gao,Jinkang Yu,Jian Lou,Songmin Ying,Daniel H. Scharf,Wen Li,Zhihua Chen
Fungal infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.
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ONCOGENE
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2020
·Vol. 39
·期 11
·2408-2423
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IF 7.971
Guan Yun-feng,Huang Qiao-ling,Ai Yuan-li,Chen Qi-tao,Zhao Wen-xiu,Wang Xiao-min,Wu Qiao,Chen Hang-zi
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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IMMUNOLOGICAL INVESTIGATIONS
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2026
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IF 2.3
Yanliuying Zhu,Xinyan Zan,Kerui Fan,Jiao Wang,Ying Zhi,Jinlin Liu,Yongqiang Yang,Li Zhang
Objective Autophagy dysfunction results in the accumulation of pro-inflammatory components and drives inflammatory injury. Transcription factor EB (TFEB) is a master regulator of autophagy and a novel target for controlling inflammatory injury. Curcumin analog C1 directly binds to and activates TFEB, but its anti-inflammatory effects remain unclear.Methods The anti-inflammatory and protective effects of curcumin analog C1 were investigated in lipopolysaccharide (LPS)-induced endotoxemia mice.Results Curcumin analog C1 reversed LPS-induced autophagy dysfunction, downregulated pyruvate kinase M2 (PKM2), and reduced pro-inflammatory cytokines including TNF–α, IL–6, and MCP–1. It also attenuated systemic abnormalities, alleviated lung injury, and decreased blood urea nitrogen (BUN), brain-type natriuretic peptide (BNP), and extracellular DNA levels.Conclusions Curcumin analog C1 exhibits potential pharmacological value in the control of inflammatory injury.Thank you for your assistance.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Dongrong Zhu,Lirong Zhao,Yue Li,Linnan Du,Dingqiao Xu,Peng Wang,Sha Liu,Liren Liu
Acute lung injury (ALI) is a life-threatening inflammatory condition with limited therapeutic options. Metabolic reprogramming, particularly PKM2-mediated glycolysis, plays a pivotal role in inflammatory responses, yet natural activators targeting this pathway remain largely unexplored. Herein, we found that seco-tanapartholide B (SB), a sesquiterpene lactone derived from the medicinal and edible herb Artemisia argy i, suppresses inflammation and glycolysis both in vitro and in vivo , thereby alleviating lipopolysaccharide (LPS)-induced ALI. Using thermal proteome profiling (TPP), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and bio-layer interferometry (BLI), we identified PKM2 as the direct molecular target of SB. LC–MS/MS analysis further revealed that SB covalently binds to Cys424 of PKM2 through its α-methylene-γ-lactone moiety, leading to enhanced pyruvate kinase activity and promoted PKM2 tetramerization. Consequently, this modification suppressed glycolysis as well as inflammation-related pathways, including NF-κB and STAT3 signaling, and reduced HIF-1α expression. Additionally, genetic knockdown of PKM2 attenuates the anti-inflammatory and glycolysis-inhibitory effects of SB in macrophages. Collectively, these findings identify SB as a natural PKM2 activator that therapeutically targets metabolic–inflammatory crosstalk in ALI. This study extends the potential application of PKM2 activators beyond oncology to inflammatory lung diseases and provides a biochemical rationale for promoting PKM2 tetramerization as a therapeutic strategy for ALI/acute respiratory distress syndrome (ARDS).
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Journal of Inflammation Research
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2021
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IF 6.922
Zhen-Hua Ying,Hui-Min Li,Wen-Ying Yu,Chen-Huan Yu
Purpose Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice. Methods The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1β, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis. Results IRD treatment at the concentrations of 12.5–50 μM significantly inhibited the productions of TNF-α, IL-1β, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20–80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191. Conclusion IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.
研究领域:
药理学
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免疫学
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细胞生物学
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分子生物学
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BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Xu Yao,Jie Zhu,Lin Li,Bo Yang,Bixia Chen,Endong Bao,Xiaohui Zhang
Severe heat stress can cause human and animal heart failure and sudden death, which is an important issue of public health worldwide. Our previous studies in animals showed that myocardial cells injury was critical in the above process, and Hsp90 induction has a definite anti-myocardial injury effect, especially through aspirin (ASA). But the mechanism has not been fully clarified. In this study, an in vitro heat stress model of chicken primary myocardial cells (CPMCs) most sensitive to heat stress was used to explore the cell injuries and corresponding molecular resistance mechanism. We found that heat stress resulted in serious oxidation stress and calcium overload in mitochondria, which destroyed the mitochondrial structure and function and then triggered the cell death mechanism of CPMCs. Hsp90 was proven to be a central regulator for resisting heat-stress injury in CPMCs mitochondria using its inhibitor and inducer (geldanamycin and ASA), respectively. The mechanism involved that Hsp90 could activate Akt and PKM2 signals to promote Bcl-2 translocation into mitochondria and its phosphorylation, thereby preventing ROS production and subsequent cell apoptosis . In addition, Hsp90 inhibited mitochondrial calcium overload to overcome MPTP opening and MMP suppression through the inhibitory effect of Raf-1-ERK activation on the CREB-IP3R pathway. This study is the first to reveal a pivotal reason for heat-stressed damage in chicken myocardial cells at subcellular level and identify an effective regulator, Hsp90, and its protective mechanisms responsible for maintaining mitochondrial homeostasis.
研究领域:
细胞生物学
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分子生物学
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心脏病学
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应激生物学
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NEUROCHEMICAL RESEARCH
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2026
·Vol. 51
·期 4
·207
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IF 4.5
Fu Jie,Zhang Shaotao,Chu Yifei,Li Jinglun,Chen Xiu
Microglia-mediated neuroinflammation is closely associated with the pathogenesis of epilepsy. Mammalian sterile-20-like kinase 4 (MST4) has been suggested a regulator of inflammation. However, the effect of MST4 on microglia neuroinflammation in epilepsy remains unclear. A pilocarpine-induced rat epilepsy model was constructed and a lipopolysaccharide (LPS)-stimulated microglia cell model was applied in the current research. Knockdown or overexpression of MST4 was established using lentivirus transfection. Electroencephalograph (EEG) was employed to measure brain activities of rats. The protein and mRNA expressions were detected using western blot and qRT-PCR, respectively. Immunofluorescent staining was conducted to detect the distribution of the proteins. TUNEL staining was performed to evaluate cell apoptosis. The protein interaction was evaluated with Co-IP assay. Our results showed that MST4 and nuclear PKM2 expressions were increased in epileptic rats compared to control and colocalized with microglia. MST4 overexpression inhibited microglia activation, the release of TNF-α and IL-1β, and improved neuronal apoptosis in epileptic rats. Furthermore, MST4 interacted with PKM2 and regulated PKM2 nuclear translocation. Inhibiting PKM2 nuclear translocation by TEPP-46 reversed the promoting effect of MST4 knockdown on microglia neuroinflammation. In summary, our study demonstrated that MST4 alleviated microglia-mediated neuroinflammation in epilepsy, and the mechanism of MST4-mediated anti-neuroinflammatory effects may be associated with the inhibition of PKM2 nuclear translocation.
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Communications Biology
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2026
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IF 5.8
Shen Jing,Zhu Lirong,Yang Ronghui,Liao Aijun
Multiple myeloma (MM) is a systemic malignancy characterized by the induction of osteolytic lesions. Cold-inducible RNA binding protein (CIRBP) has garnered attention in cancer research due to its dual role as either an oncogene or a tumor suppressor. In this study, publicly available single-cell RNA sequencing data, MM cell lines, and an in vivo xenograft model are utilized to assess the biological significance of CIRBP in MM. Analysis reveals frequent communication between MM cells and macrophages, alongside decreased CIRBP expression in patients. Functionally, CIRBP overexpression in MM cells inhibits short- and long-term viability, suppresses proliferation, and reduces tumor burden in vitro and in vivo. Furthermore, co-culture experiments confirm that CIRBP -expressing MM cells suppress macrophage chemotaxis and macrophage alternative activation, while CIRBP knockdown has opposite effects. Mechanistically, CIRBP binds to intron1 of pyruvate kinase M2 ( PKM2 ) precursor messenger RNA (pre-mRNA), inhibiting its splicing and promoting its nonsense-mediated decay, ultimately leading to downregulation of PKM2 . Elevated levels of PKM2 rescue the CIRBP-mediated suppression of macrophage chemotaxis and macrophage alternative activation. Our findings support the notion of CIRBP as a candidate tumor suppressor in MM and unveil a post-transcriptional regulatory mechanism governing PKM2-mediated macrophage plasticity.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Simiao Qiao,Fanshu Li,Jia Huang,Xiaoqian Wu,Xiaoying Cao,Xifeng Zhang,Zhifeng Wei
This study was designed to clarify the reason for PM 2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM 2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM 2.5 via controlling “aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)” axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM 2.5 -induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM 2.5 activated “AHR-HSP90” axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM 2.5 , and was suggested as a potential compound to combat the exacerbation of asthma.
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PHYTOMEDICINE
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2026
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IF 11.3
Jing-hang Li,Xian-Feng Yu,Shu-Ming Shi,Tian Lan,dan Liu,Jia-hui Leng,Li-Ying Liu,Yu-Yan He,Guan-Lin Jia,Hong-jie Xu,Il-keun Kong,Ming-Jun Zhang,Yong-Xun Jin
Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that severely impacts female fertility. The natural dihydrochalcone trilobatin (TLB) has shown potential in managing metabolic diseases; however, its therapeutic effect on PCOS and the underlying mechanisms remain unexplored. Purpose To investigate the therapeutic potential of TLB for PCOS and to elucidate the mechanistic basis, focusing on glycolytic metabolism and mitochondrial function in granulosa cells (GCs). Methods A dehydroepiandrosterone (DHEA) -induced PCOS rat model was established and treated with two different doses of TLB or metformin.Therapeutic effects were assessed based on estrous cyclicity, ovarian morphology, serum hormone levels, and the HOMA-IR index. Key targets were identified through integrated metabolomics and bioinformatics analyses. The mechanism was further validated in vitro using dihydrotestosterone (DHT)-induced primary rat GCs, combined with molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, co-immunoprecipitation (CO-IP), and Seahorse metabolic analysis. Results TLB administration alleviated estrous cycle disruption, improved ovarian morphology, and normalized serum testosterone, luteinizing hormone, and HOMA-IR index in PCOS rats. Metabolomics and bioinformatics analyses identified SIRT2 as a primary target of TLB. Mechanistically, TLB targets SIRT2, promoting the deacetylation of pyruvate kinase M2 (PKM2) at the K305 site. This deacetylation enhanced PKM2 tetramerization and enzymatic activity, thereby ameliorating the glycolytic imbalance in GCs, as evidenced by reduced pyruvate accumulation and restored lactate production. Furthermore, TLB, via the SIRT2/PKM2 axis, improved mitochondrial function, supported by the recovery of ATP production, mitochondrial membrane potential, and mitochondrial permeability transition pore integrity, ultimately suppressing GC apoptosis. Conclusion Our findings demonstrate that TLB alleviates ovarian PCOS phenotypes by targeting SIRT2 to promote PKM2 deacetylation at K305, which effectively corrects glycolytic flux and restores mitochondrial function in GCs.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
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IF 4.7
Li Qianyu,Wang Huiyue,Chen Nan,Liu Xue,Li Yongle,Chen Lei,Gan Lu,Luan Yong
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m 6 A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m 6 A reader protein YTHDF2, which recognizes m 6 A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.
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Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Ya Chen,Yuan Jiang,Xinyu Huang,Lin Chen,Hao Yang,Jian Zhao,Beibei Liang
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, with a high incidence and mortality rate. Glucose metabolism reprogramming is a major characteristic of tumor cells. Increasing evidence indicates that aerobic glycolysis is associated with tumor growth and insensitivity to chemotherapy. Cordycepin inhibits the growth of HCC cells, but the mechanism is yet to be elucidated. Herein, in vitro and in vivo methods were utilized to investigate the cordycepin-inhibited growth of HCC by regulating the metabolic pathway of aerobic glycolysis. In vitro analyses using colony formation and flow cytometry revealed that cordycepin inhibits HCC cells’ proliferation and promotes apoptosis. In addition, cordycepin reduced the production of lactic acid and pyruvate, reduced the uptake of glucose, and decreased the extracellular acidification in HCC cells. Specifically, cordycepin inhibited the expression of HK2, LDHA, and PKM2 in aerobic glycolysis via the AMPK-Akt pathway. Taken together, these findings revealed that cordycepin reduces the tumor energy supply and decreases lactic acid production, thereby inhibiting the growth of HCC cells by regulating the metabolic pathway of aerobic glycolysis. These findings might provide novel insights into the mechanisms underlying cordycepin-mediated inhibition of tumor growth as well as a new treatment for HCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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