Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Background: The role of Pyruvate kinase M2 (PKM2) in intestinal ischemia-reperfusion (I/R) was investigated in this study, with a focus on the mechanism of dimeric PKM2 in ferroptosis.
Methods: The in vivo and in vitro models of intestinal ischemia-reperfusion were constructed and in vitro and in vivo evaluations were performed using a variety of techniques.
Results: HMGB1 and dimeric PKM2 were highly expressed in intestinal I/R mice. Dimeric PKM2 inhibitors (ML265) and HMGB1 inhibitors (Glycyrrhizin) reduced ferroptosis in vivo and in vitro. ML265 decreased glucose uptake, lactate, GLUT1, ENO1, LDHA, and PDK1 levels. Importantly, HMGB1 knockdown completely counterbalanced the promoting effect of PKM2 overexpression on ferroptosis, while ACSL4 knockdown or GPX4 overexpression partially revoked the promoting effect of PKM2 overexpression on ferroptosis. HMGB1 overexpression completely prevented the inhibiting effect of PKM2 knockdown on ferroptosis. Lactate promoted pan kla and H4K12la levels in H/R-induced Caco-2 cells and promoted ferroptosis. ML265 reversed the phenomenon. Moreover, CoIP results showed that PKM2 directly bound to p300. ChIP-qPCR results showed that the concentration of dimeric PKM2 (and nuclear PKM2) and p300 on HMGB1 promoter increased in H/R group. ML265 reduced the enrichment of p300 on HMGB1 promoter. Sh-p300 reduced H4K12la enrichment on HMGB1 promoter. In addition, oe-p300 disrupted the effect of ML265 on H/R-induced Caco-2 cells.
Conclusions: Our results suggested that dimeric PKM2 induced ferroptosis in intestinal I/R by stimulating lactylation-mediated HMGB1 transcription activation via the lactic acid/p300 axis, which may provide new targets for treatment of intestinal I/R injury.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbadis.2025.167998 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
An Optimized Enzyme-Coupled Spectrophotometric Method for Measuring Pyruvate Kinase Kinetics.
Bio Protoc
August 2025
Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India.
Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, producing ATP in the final step of glycolysis. Unlike other isoforms, PKM2 is uniquely regulated, shifting between active tetramers and less active dimers to balance energy production with biosynthetic demands. This flexibility is exploited in cancer cells to support the Warburg effect and anabolic growth.
View Article and Find Full Text PDFAnalysis of an alternatively spliced variant of mouse Pklr gene encoding a novel isoform with distinct N-terminal.
Biochem Biophys Res Commun
August 2025
Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India. Electronic address:
Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism. Mammalian pyruvate kinase functions as a tetrameric protein composed of identical subunits, which adopt a dimer-of-dimers configuration. Each monomer features a single active site and consists of three primary domains designated A, B and C, and a small N-terminal domain.
View Article and Find Full Text PDFPoly-L-arginine induces asthma pyroptosis in lung epithelial cells by promoting nuclear translocation of the PKM2 dimer.
Cell Signal
August 2025
Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei 230031, China; Anhui Geriatric Institute, Hefei 230031, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation, Hefei 230031, China. Electronic
Inflammation is a principal mechanism in asthma pathogenesis. Activated eosinophils (EOSs) play an important role in the chronic inflammatory environment of asthma by releasing major basic protein (MBP) and other cationic granule proteins. Pyroptosis has been demonstrated to participate in asthma-related inflammation.
View Article and Find Full Text PDFDiscovery of PKM2 activators from Aconiti Lateralis Radix Praeparata via computer-aided drug design and experimental validation.
Fitoterapia
August 2025
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing, China. Electronic address:
Computer-aided drug design (CADD) provides unique benefits for discovering and optimizing lead compounds. Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is a traditional herbal medicine widely used in China and other Asian countries. This study employed virtual screening, molecular dynamics simulations, and experimental validation to identify activators of pyruvate kinase M2 (PKM2) from Fuzi alkaloids.
View Article and Find Full Text PDFDimeric PKM2 induces ferroptosis from intestinal ischemia/reperfusion in mice by histone H4 lysine 12 lactylation-mediated HMGB1 transcription activation through the lactic acid/p300 axis.
Biochim Biophys Acta Mol Basis Dis
July 2025
Department of Pediatric Surgery, Clinical Research Center for Pediatric Solid Tumors in Hunan Province, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's hospital), Changsha 410007, P
Background: The role of Pyruvate kinase M2 (PKM2) in intestinal ischemia-reperfusion (I/R) was investigated in this study, with a focus on the mechanism of dimeric PKM2 in ferroptosis.
Methods: The in vivo and in vitro models of intestinal ischemia-reperfusion were constructed and in vitro and in vivo evaluations were performed using a variety of techniques.
Results: HMGB1 and dimeric PKM2 were highly expressed in intestinal I/R mice.